Therapeutic agent delivery device

ABSTRACT

A system for storing and delivering a predetermined amount of fluid includes a syringe including a barrel, a flange disposed at the proximal end of the barrel, and a plunger assembly configured to be received in the lumen of the barrel. The plunger assembly includes a piston and a plunger rod. The plunger rod is removably couplable to the piston at the distal end of the plunger rod and includes a thumb press flange at the proximal end of the plunger rod. The system further includes a stop feature that is removably couplable to the syringe or the plunger assembly. The stop feature is configured to arrest distal advancement of the plunger assembly relative to the syringe when the plunger assembly reaches a predetermined position relative to the syringe. The stop thus ensures that a predetermined amount of fluid remains in the barrel.

PRIORITY

This application is a continuation of U.S. application Ser. No.14/843,350, entitled “Therapeutic Agent Delivery Device,” filed Sep. 2,2015, issued as U.S. Pat. No. 10,258,502 on Apr. 16, 2019.

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/052,038, entitled “Measurement Tab for Micro Volumetric CellSolution Delivery,” filed Sep. 18, 2014, the disclosure of which isincorporated by reference herein.

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/052,043, entitled “Pneumatic Pressure Control Delivery System,”filed Sep. 18, 2014, the disclosure of which is incorporated byreference herein.

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/052,059, entitled “Snap Collar Syringe Adaptor,” filed Sep. 18,2014, the disclosure of which is incorporated by reference herein.

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/052,074, entitled “Syringe Vessel with Detachable Plunger Rod,”filed Sep. 18, 2014, the disclosure of which is incorporated byreference herein.

JOINT RESEARCH STATEMENT

Subject matter disclosed in this application was developed and theclaimed invention was made by, or on behalf of, one or more parties to ajoint research agreement that was in effect on or before the effectivefiling date of the claimed invention. The claimed invention was made asa result of activities undertaken within the scope of the joint researchagreement. The parties to the joint research agreement include EthiconEndo-Surgery, Inc. and Janssen Research & Development, LLC.

BACKGROUND

The human eye comprises several layers. The white outer layer is thesclera, which surrounds the choroid layer. The retina is interior to thechoroid layer. The sclera contains collagen and elastic fiber, providingprotection to the choroid and retina. The choroid layer includesvasculature providing oxygen and nourishment to the retina. The retinacomprises light sensitive tissue, including rods and cones. The maculais located at the center of the retina at the back of the eye, generallycentered on an axis passing through the centers of the lens and corneaof the eye (i.e., the optic axis). The macula provides central vision,particularly through cone cells.

Macular degeneration is a medical condition that affects the macula,such that people suffering from macular degeneration may experience lostor degraded central vision while retaining some degree of peripheralvision. Macular degeneration may be caused by various factors such asage (also known as “AMD”) and genetics. Macular degeneration may occurin a “dry” (nonexudative) form, where cellular debris known as drusenaccumulates between the retina and the choroid, resulting in an area ofgeographic atrophy. Macular degeneration may also occur in a “wet”(exudative) form, where blood vessels grow up from the choroid behindthe retina. Even though people having macular degeneration may retainsome degree of peripheral vision, the loss of central vision may have asignificant negative impact on the quality of life. Moreover, thequality of the remaining peripheral vision may be degraded and in somecases may disappear as well. It may therefore be desirable to providetreatment for macular degeneration in order to prevent or reverse theloss of vision caused by macular degeneration. In some cases it may bedesirable to provide such treatment in a highly localized fashion, suchas by delivering a therapeutic substance in the subretinal layer (underthe neurosensory layer of the retina and above the retinal pigmentepithelium) directly adjacent to the area of geographic atrophy, nearthe macula. However, since the macula is at the back of the eye andunderneath the delicate layer of the retina, it may be difficult toaccess the macula in a practical fashion.

While a variety of surgical methods and instruments have been made andused to treat an eye, it is believed that no one prior to the inventorshas made or used the invention described in the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

While the specification concludes with claims which particularly pointout and distinctly claim this technology, it is believed this technologywill be better understood from the following description of certainexamples taken in conjunction with the accompanying drawings, in whichlike reference numerals identify the same elements and in which:

FIG. 1 depicts a perspective view of an exemplary instrument forsubretinal administration of a therapeutic agent from a suprachoroidalapproach;

FIG. 2 depicts a side elevational view of the instrument of FIG. 1;

FIG. 3 depicts another side elevational view of the instrument of FIG.1, with a locking member removed;

FIG. 4 depicts another side elevational view of the instrument of FIG.1, with an actuation member advanced distally to extend the needledistally from the cannula;

FIG. 5 depicts a perspective view of the distal end of an exemplarycannula that may be incorporated into the instrument of FIG. 1;

FIG. 6 depicts a cross-sectional view of the cannula of FIG. 5, with thecross-section taken along line 6-6 of FIG. 5;

FIG. 7 depicts a perspective view of another exemplary alternativeinstrument for subretinal administration of a therapeutic agent from asuprachoroidal approach;

FIG. 8 depicts a perspective view of an exemplary suture measurementtemplate for use in an exemplary method for the subretinaladministration of a therapeutic agent from a suprachoroidal approach;

FIG. 9A depicts a top plan view of an eye of a patient, with surroundingstructures of the eye immobilized and a chandelier installed;

FIG. 9B depicts a top plan view of the eye of FIG. 9A, with the templateof FIG. 8 disposed on the eye;

FIG. 9C depicts a top plan view of the eye of FIG. 9A, with a pluralityof markers disposed on the eye;

FIG. 9D depicts a top plan view of the eye of FIG. 9A, with a sutureloop attached to the eye;

FIG. 9E depicts a top plan view of the eye of FIG. 9A, with a sclerotomybeing performed;

FIG. 9F depicts a top plan view of the eye of FIG. 9A, with theinstrument of FIG. 1 being inserted through the sclerotomy opening andin between the sclera and choroid of the eye;

FIG. 9G depicts a top plan view of the eye of FIG. 9A, with theinstrument of FIG. 1 under direct visualization at the back of the eye,between the sclera and choroid;

FIG. 9H depicts a top plan view of the eye of FIG. 9A, with the needleof the instrument of FIG. 1 being advanced under direct visualization atthe back of the eye, pressing against the outer surface of the choroidcausing the choroid to ‘tent’;

FIG. 9I depicts a top plan view of the eye of FIG. 9A, with the needledispensing a leading bleb under direct visualization at the back of theeye, the needle between the sclera and choroid, and the leading bleb inthe sub retinal space between the choroid and a retina;

FIG. 9J depicts a top plan view of the eye of FIG. 9A, with the needledispensing a therapeutic agent to the eye at the back of the eye,between the sclera and choroid;

FIG. 10A depicts a cross-sectional view of the eye of FIG. 9A, with thecross-section taken about line 10A-10A of FIG. 9A;

FIG. 10B depicts a cross-sectional view of the eye of FIG. 9A, with thecross-section taken about line 10B-10B of FIG. 9E;

FIG. 10C depicts a cross-sectional view of the eye of FIG. 9A, with thecross-section taken about line 10C-10C of FIG. 9F;

FIG. 10D depicts a cross-sectional view of the eye of FIG. 9A, with thecross-section taken about line 10D-10D of FIG. 9G;

FIG. 10E depicts a cross-sectional view of the eye of FIG. 9A, with thecross-section taken about line 10E-10E of FIG. 9H;

FIG. 10F depicts a cross-sectional view of the eye of FIG. 9A, with thecross-section taken about line 10F-10F of FIG. 9I;

FIG. 10G depicts a cross-sectional view of the eye of FIG. 9A, with thecross-section taken about line 10G-10G of FIG. 9J;

FIG. 11A depicts a detailed cross-sectional view of the eye of FIG. 9Adepicted in the state shown in FIG. 10E;

FIG. 11B depicts a detailed cross-sectional view of the eye of FIG. 9Adepicted in the state shown in FIG. 10F;

FIG. 11C depicts a detailed cross-sectional view of the eye of FIG. 9Adepicted in the state shown in FIG. 10G;

FIG. 12A depicts an exemplary syringe assembly that may be used with theinstruments of FIGS. 1 and 7, with a syringe of the syringe assemblydrawing fluid from a fluid source;

FIG. 12B depicts a perspective view of the syringe assembly of FIG. 12A,with the measurement tab of the syringe assembly engaged with a plungerof the syringe;

FIG. 12C depicts a perspective view of the syringe assembly of FIG. 12A,with the plunger advanced to a position governed by the measurement tab,and with the syringe in communication with an instrument for subretinaladministration of a therapeutic agent from a suprachoroidal approach;

FIG. 12D depicts a perspective view of the syringe of FIG. 12A, with themeasurement tab removed from the plunger, and with the syringe incommunication with the instrument;

FIG. 12E depicts a perspective view of the syringe of FIG. 12A, with theplunger assembly having been advanced distally to dispense the contentsof the syringe to the instrument;

FIG. 13A depicts a perspective view of the syringe of the syringeassembly of FIG. 12A, showing the plunger rod of the plunger assemblybeing rotated relative to the barrel;

FIG. 13B depicts a perspective view of the syringe of FIG. 12A, with theplunger rod having been removed from the barrel;

FIG. 13C depicts a perspective view of the barrel of the syringe of FIG.12A;

FIG. 14A depicts a side cross-sectional perspective view of the syringeassembly of FIG. 12A;

FIG. 14B depicts a side cross-sectional perspective view of the syringeof FIG. 12A, with the plunger rod having been removed from the barrel;

FIG. 15A depicts a top cross-sectional view of the syringe assembly ofFIG. 12A, with the measurement tab laterally separated from the plungerrod;

FIG. 15B depicts a top cross-sectional view of the syringe assembly ofFIG. 12A, with the measurement tab laterally secured to the plunger rod;

FIG. 16 depicts a perspective view of an exemplary syringe adapter thatis configured for use with the syringe of FIG. 12A;

FIG. 17 depicts a side cross-sectional view of the syringe adapter ofFIG. 16;

FIG. 18 depicts a perspective view of an exemplary engagement collarthat is configured for use with the syringe of FIG. 12A and the syringeadapter of FIG. 16;

FIG. 19 depicts a perspective cross-sectional view of the engagementcollar of FIG. 18;

FIG. 20A depicts an exploded perspective view of the syringe of FIG.12A, the syringe adapter of FIG. 16, and the engagement collar of FIG.18;

FIG. 20B depicts a partially exploded perspective view of the syringe ofFIG. 12A, the syringe adapter of FIG. 16, and the engagement collar ofFIG. 18, with the syringe adapter inserted into an end of the syringeand the engagement collar separated from the syringe and the syringeadapter;

FIG. 20C depicts a perspective view of the syringe of FIG. 12A, thesyringe adapter of FIG. 16, and the engagement collar of FIG. 18, withall of the components assembled together;

FIG. 21A depicts a side cross-sectional view of the syringe of FIG. 12Aand the syringe adapter of FIG. 16, with the syringe adapter separatedfrom an end of the syringe;

FIG. 21B depicts a side cross-sectional view of the syringe of FIG. 12Aand the syringe adapter of FIG. 16, with the syringe adapter insertedinto the end of the syringe;

FIG. 21C depicts a side cross-sectional view of the syringe of FIG. 12A,the syringe adapter of FIG. 16, and the engagement collar of FIG. 18,with all of the components assembled together;

FIG. 22 depicts a perspective view of an exemplary alternative syringethat may be used with the instruments of FIGS. 1 and 7;

FIG. 23 depicts a side cross-sectional view of the syringe of FIG. 22;

FIG. 24 depicts a perspective view of an exemplary alternative syringeadapter, configured for use with the syringe of FIG. 22;

FIG. 25 depicts a side cross-sectional view of the syringe adapter ofFIG. 24;

FIG. 26A depicts an exploded perspective view of the syringe of FIG. 22,the syringe adapter of FIG. 24, and an exemplary alternative engagementcollar;

FIG. 26B depicts a partially exploded perspective view of the syringeFIG. 22, the syringe adapter of FIG. 24, and the engagement collar ofFIG. 26A, with the syringe adapter positioned over an end of the syringeand the engagement collar separated from the syringe and the syringeadapter;

FIG. 26C depicts a perspective view of the syringe of FIG. 22, thesyringe adapter of FIG. 24, and the engagement collar of FIG. 26A, withall of the components assembled together;

FIG. 27A depicts a side cross-sectional view of the syringe of FIG. 22,the syringe adapter of FIG. 24, with the syringe adapter separated froman end of the syringe;

FIG. 27B depicts a side cross-sectional view of the syringe of FIG. 22and the syringe adapter of FIG. 24, with the syringe adapter positionedover the end of the syringe;

FIG. 27C depicts a side cross-sectional view of the syringe of FIG. 22,the syringe adapter of FIG. 24, and the engagement collar of FIG. 26A,with all of the components assembled together;

FIG. 28 depicts a perspective view of an exemplary pneumatic pressurecontrol delivery system coupled with the syringe of FIG. 12A, thesyringe of FIG. 22, and an instrument for subretinal administration of atherapeutic agent from a suprachoroidal approach;

FIG. 29 depicts a perspective view of another exemplary fluid deliveryassembly that may be used with the instruments of FIGS. 1 and 7;

FIG. 30 depicts an exploded perspective view of the fluid deliveryassembly of FIG. 29;

FIG. 31 depicts a perspective view of a first spacer of the fluiddelivery assembly of FIG. 29;

FIG. 32 depicts a perspective view of a second spacer of the fluiddelivery assembly of FIG. 29;

FIG. 33 depicts another perspective view of the second spacer of FIG.32;

FIG. 34 depicts a perspective view of a third spacer of the fluiddelivery assembly of FIG. 29;

FIG. 35 depicts an partial side elevational view of the fluid deliveryassembly of FIG. 29, showing the spacers secured to each other and to asyringe assembly;

FIG. 36A depicts a perspective view of a syringe assembly of the fluiddelivery assembly of FIG. 29, coupled with a fluid source, with aplunger of the syringe assembly in a fully advanced position;

FIG. 36B depicts a perspective view of the syringe assembly and fluidsource of FIG. 36A, with the plunger in a retracted position;

FIG. 36C depicts a perspective view of the spacers of the fluid deliveryassembly of FIG. 29 secured to the syringe assembly of FIG. 36A, withthe plunger in a first partially advanced position;

FIG. 36D depicts a perspective view of the fluid delivery assembly ofFIG. 29, with the third spacer removed from the second spacer, and withthe plunger in the first partially advanced position;

FIG. 36E depicts a perspective view of the fluid delivery assembly ofFIG. 29, with the third spacer removed from the second spacer, and withthe plunger in a second partially advanced position;

FIG. 36F depicts a perspective view of the fluid delivery assembly ofFIG. 29, with the second spacer removed from the first spacer, and withthe plunger in the second partially advanced position; and

FIG. 36G depicts a perspective view of the fluid delivery assembly ofFIG. 29, with the second spacer removed from the first spacer, and withthe plunger in a third partially advanced position.

The drawings are not intended to be limiting in any way, and it iscontemplated that various embodiments of the technology may be carriedout in a variety of other ways, including those not necessarily depictedin the drawings. The accompanying drawings incorporated in and forming apart of the specification illustrate several aspects of the presenttechnology, and together with the description serve to explain theprinciples of the technology; it being understood, however, that thistechnology is not limited to the precise arrangements shown.

DETAILED DESCRIPTION

The following description of certain examples of the technology shouldnot be used to limit its scope. Other examples, features, aspects,embodiments, and advantages of the technology will become apparent tothose skilled in the art from the following description, which is by wayof illustration, one of the best modes contemplated for carrying out thetechnology. As will be realized, the technology described herein iscapable of other different and obvious aspects, all without departingfrom the technology. Accordingly, the drawings and descriptions shouldbe regarded as illustrative in nature and not restrictive.

It is further understood that any one or more of the teachings,expressions, embodiments, examples, etc. described herein may becombined with any one or more of the other teachings, expressions,embodiments, examples, etc. that are described herein. Thefollowing-described teachings, expressions, embodiments, examples, etc.should therefore not be viewed in isolation relative to each other.Various suitable ways in which the teachings herein may be combined willbe readily apparent to those of ordinary skill in the art in view of theteachings herein. Such modifications and variations are intended to beincluded within the scope of the claims.

For clarity of disclosure, the terms “proximal” and “distal” are definedherein relative to a surgeon or other operator grasping a surgicalinstrument having a distal surgical end effector. The term “proximal”refers the position of an element closer to the surgeon or otheroperator and the term “distal” refers to the position of an elementcloser to the surgical end effector of the surgical instrument andfurther away from the surgeon or other operator.

I. Exemplary Instrument with Slider Articulation Feature

FIGS. 1-4 show an exemplary instrument (10) that is configured for usein a procedure for the subretinal administration of a therapeutic agentto an eye of a patient from a suprachoroidal approach. Instrument (10)comprises a flexible cannula (20), a body (40), and a slidable (60).Cannula (20) extends distally from body (40) and has a generallyrectangular cross section. Cannula (20) is generally configured tosupport a needle (30) that is slidable within cannula (20), as will bedescribed in greater detail below.

In the present example, cannula (20) comprises a flexible material suchas Polyether block amide (PEBA), which may be manufactured under thetrade name PEBAX. Of course, any other suitable material or combinationof materials may be used. Also in the present example, cannula (20) hasa cross-sectional profile dimension of approximately 2.0 mm by 0.8 mm,with a length of approximately 80 mm. Alternatively, any other suitabledimensions may be used.

As will be described in greater detail below, cannula (20) is flexibleenough to conform to specific structures and contours of the patient'seye, yet cannula (20) has sufficient column strength to permitadvancement of cannula (20) between the sclera and choroid of patient'seye without buckling. Several factors may contribute to suitableflexibility of cannula (20). For instance, the durometer of the materialused to construct cannula (20) at least partially characterizes theflexibility of cannula (20). By way of example only, the material thatis used to form cannula (20) may have a shore hardness of approximately27 D, approximately 33 D, approximately 42 D, approximately 46 D, or anyother suitable shore hardness. It should be understood that the shorehardness may fall within the range of approximately 27 D toapproximately 46 D; or more particularly within the range ofapproximately 33 D to approximately 46 D; or more particularly withinthe range of approximately 40 D to approximately 45 D. The particularcross-sectional shape of cannula (20) may also at least partiallycharacterize the flexibility of cannula (20). Additionally, thestiffness of needle (30) disposed within cannula (20) may at leastpartially characterize the flexibility of cannula (20).

In the present example, the flexibility of cannula (20) may bequantified by calculating a flexural stiffness for cannula (20).Flexural stiffness is calculated by the product of the elastic modulusand the area moment of inertia. By way of example only, one exemplarymaterial that may be used to form cannula (20) may have a shore hardnessof D27, an elastic modulus (E) of 1.2×10⁷ N/m², and an area moment ofinertia (I_(x)) of 5.52×10⁻¹⁴ m⁴, providing a calculated flexuralstiffness about the x-axis at 0.7×10⁻⁶ Nm². Another exemplary materialthat may be used to form cannula (20) may have a shore hardness of D33,an elastic modulus (E) of 2.1×10⁷ N/m², and an area moment of inertia(I_(x)) of 5.52×10⁻¹⁴ m⁴, providing a calculated flexural stiffnessabout the x-axis at 1.2×10⁻⁶ Nm². Another exemplary material that may beused to form cannula (20) may have a shore hardness of D42, an elasticmodulus (E) of 7.7×10⁷ N/m², and an area moment of inertia (I_(x)) of5.52×10⁻¹⁴ m⁴, providing a calculated flexural stiffness about thex-axis at 4.3×10⁻⁶ Nm². Another exemplary material that may be used toform cannula (20) may have a shore hardness of D46, an elastic modulus(E) of 17.0×10⁷ N/m², and an area moment of inertia (I_(x)) of5.52×10⁻¹⁴ m⁴, providing a calculated flexural stiffness about thex-axis at 9.4×10⁻⁶ Nm². Thus, by way of example only, the flexuralstiffness of cannula (20) may fall within the range of approximately0.7×10⁻⁶ Nm² to approximately 9.4×10⁻⁶ Nm²; or more particularly withinthe range of approximately 1.2×10⁻⁶ Nm² to approximately 9.4×10⁻⁶ Nm²;or more particularly within the range of approximately 2.0×10⁻⁶ Nm² toapproximately 7.5×10⁻⁶ Nm²; or more particularly within the range ofapproximately 2.0×10⁻⁶ Nm² to approximately 6.0×10⁻⁶ Nm²; or moreparticularly within the range of approximately 3.0×10⁻⁶ Nm² toapproximately 5.0×10⁻⁶ Nm²; or more particularly within the range ofapproximately 4.0×10⁻⁶ Nm² to approximately 5.0×10⁻⁶ Nm².

In the present example, the flexibility of cannula (20) may also bequantified by the following formula:

$\begin{matrix}{\delta = \frac{{FL}^{3}}{48\mspace{14mu}{EI}}} & (1)\end{matrix}$

In the above equation, flexural stiffness (EI) is calculatedexperimentally by deflecting cannula (20) having a fixed span (L) a setdistance to yield a predetermined amount of deflection (δ). The amountof force (F) required for such a deflection may then be recorded. Forinstance, when using such a method cannula (20) may have a span of 0.06m and may be deflected for a given distance. By way of example only, oneexemplary material that may be used to form cannula (20) may require aforce of 0.0188 N to achieve a deflection of 0.0155 m, providing acalculated flexural stiffness about the x-axis of 5.5×10⁻⁶ Nm². Inanother exemplary material that may be used to form cannula (20) mayrequire a force of 0.0205 N to achieve a deflection of 0.0135 m,providing a calculated flexural stiffness about the x-axis of 6.8×10⁻⁶Nm². In still another exemplary material that may be used to formcannula (20) may require a force of 0.0199 N to achieve a deflection of0.0099 m, providing a calculated flexural stiffness about the x-axis of9.1×10⁻⁶ Nm². In yet another exemplary material that may be used to formcannula (20) may require a force of 0.0241 N to achieve a deflection of0.0061 m, providing a calculated flexural stiffness about the x-axis of1.8×10⁻⁶ Nm². In yet another exemplary material that may be used to formcannula (20) may require a force of 0.0190 N to achieve a deflection0.0081 m, providing a calculated flexural stiffness about the x-axis of1.0×10⁻⁶ Nm². In yet another exemplary material that may be used to formcannula (20) may require a force of 0.0215 N to achieve a deflection of0.0114 m, providing a calculated flexural stiffness about the x-axis of8.4×10⁻⁶ Nm². In yet another exemplary material that may be used to formcannula (20) may require a force of 0.0193 N to achieve a deflection of0.0170 m, providing a calculated flexural stiffness about the x-axis of5.1×10⁻⁶ Nm². In yet another exemplary material that may be used to formcannula (20) may require a force of 0.0224 N to achieve a deflection of0.0152 m, providing a calculated flexural stiffness about the x-axis of6.6×10⁻⁶ Nm². In yet another exemplary material that may be used to formcannula (20) may require a force of 0.0183 N to achieve a deflection of0.0119 m, providing a calculated flexural stiffness about the x-axis of6.9×10⁻⁶ Nm². In yet another exemplary material that may be used to formcannula (20) may require a force of 0.0233 N to achieve a deflection of0.0147 m, providing a calculated flexural stiffness about the x-axis of7.1×10⁻⁶ Nm². In yet another exemplary material that may be used to formcannula (20) may require a force of 0.0192 N to achieve a deflection of0.0122, providing a calculated flexural stiffness about the x-axis of7.1×10⁻⁶ Nm². In yet another exemplary material that may be used to formcannula (20) may require a force of 0.0201 N to achieve a deflection of0.0201, providing a calculated flexural stiffness about the x-axis of4.5×10⁻⁶ Nm². Thus, by way of example only, the flexural stiffness ofcannula (20) may fall within the range of approximately 1.0×10⁻⁶ Nm² toapproximately 9.1×10⁻⁶ Nm². It should be understood that in otherexamples, the flexural stiffness of cannula may fall within the range ofapproximately 0.7×10⁻⁶ Nm² to approximately 11.1×10⁻⁶ Nm²; or moreparticularly within the range of approximately 2.0×10⁻⁶ Nm² toapproximately 6.0×10⁻⁶ Nm².

Needle (30) may have a flexural stiffness that differs from the flexuralstiffness of cannula (20). By way of example only, needle (30) may beformed of a nitinol material that has an elastic modulus (E) of 7.9×10¹⁰N/m², and an area moment of inertia (I_(x)) of 2.12×10⁻¹⁷ m⁴, providinga calculated flexural stiffness about the x-axis at 1.7×10⁻⁶ Nm². By wayof further example only, the flexural stiffness of needle (30) may fallwithin the range of approximately 0.5×10⁻⁶ Nm² to approximately 2.5×10⁻⁶Nm²; or more particularly within the range of approximately 0.75×10⁻⁶Nm² to approximately 2.0×10⁻⁶ Nm²; or more particularly within the rangeof approximately 1.25×10⁻⁶ Nm² to approximately 1.75×10⁻⁶ Nm².

As can be seen in FIGS. 5 and 6, cannula (20) comprises two side lumens(22) and a single central lumen (24) extending longitudinally throughcannula (20) and terminating at an atraumatic, beveled distal end (26).A beveled lateral opening (28) is located proximal to beveled distal end(26). Side lumens (22) contribute to the flexibility of cannula (20).Although lumens (22, 24) are shown as being open at beveled distal end(26), it should be understood that in some examples, side lumens (22,24) may be optionally closed at beveled distal end (26). As will bedescribed in greater detail below, central lumen (24) is configured toreceive needle (30) and a needle guide (80). In some versions, anoptical fiber (not shown) is also disposed in central lumen (24)alongside needle (30). Such an optical fiber may be used to provideillumination and/or optical feedback.

Beveled distal end (26) is generally beveled to provide separationbetween the sclera and choroid layers to enable cannula (20) to beadvanced between such layers while not inflicting trauma to the scleraor choroid layers. In the present example, beveled distal end (26) isbeveled at an angle of approximately 15° relative to the longitudinalaxis of cannula (20) in the present example. In other examples, beveleddistal end (26) may have a bevel angle within the range of approximately5° to approximately 50°; or more particularly within the range ofapproximately 5° to approximately 40°; or more particularly within therange of approximately 10° to approximately 30°; or more particularlywithin the range of approximately 10° to approximately 20°.

A needle guide (80) is disposed within lumen (24) such that the distalend of needle guide (80) abuts beveled lateral opening (28). Needleguide (80) is generally configured to direct needle (30) upwardly alongan exit axis (EA) that is obliquely oriented relative to thelongitudinal axis (LA) of cannula (20) through beveled opening (28) ofcannula (20). Needle guide (80) may be formed of plastic, stainlesssteel, and/or any other suitable biocompatible material(s). The shape ofneedle guide (80) is configured for insertion into central lumen (24).In the present example, needle guide (80) is secured within centrallumen (24) by a press or interference fit, although in other examples,adhesives and/or mechanical locking mechanisms may be used to secureneedle guide (80).

As can best be seen in FIG. 6, needle guide (80) defines an internallumen (84) that is configured to slidably receive needle (30). Inparticular, internal lumen (84) includes a generally straight proximalportion (86) and a curved distal portion (88). Straight proximal portion(86) corresponds to the longitudinal axis (LA) of cannula (20), whilecurved distal portion (88) curves upwardly away from the longitudinalaxis of cannula (20). Curved distal portion (88) of the present exampleis curved to direct needle (30) along an exit axis (EA) that extendsdistally from cannula (20) at an angle of approximately 7° toapproximately 9° relative to the longitudinal axis (LA) of cannula (20).It should be understood that such an angle may be desirable to deflectneedle (30) in a direction to ensure penetration of needle into thechoroid (306) and to minimize the possibility of needle (30) continuingbeneath the choroid (306) through the suprachoroidal space (as opposedto penetrating through the choroid (306)) and the possibility of retinalperforation. By way of further example only, curved distal portion (88)may urge needle (30) to exit cannula (20) along an exit axis (EA) thatis oriented at an angle within the range of approximately 5° toapproximately 30° relative to the longitudinal axis (LA) of cannula(20); or more particularly within the range of approximately 5° toapproximately 20° relative to the longitudinal axis (LA) of cannula(20); or more particularly within the range of approximately 5° toapproximately 10° relative to the longitudinal axis (LA) of cannula(20).

Needle (30) is in the form of an inner cannula has a sharp distal end(32) and defines an internal lumen (34). Distal end (32) of the presentexample has a lancet configuration. In some other versions, distal end(32) has a tri-bevel configuration or any other configuration asdescribed in U.S. patent application Ser. No. 14/619,256, entitled“Method and Apparatus for Subretinal Administration of TherapeuticAgent,” filed Feb. 11, 2015, issued as U.S. Pat. No. 10,226,379 on Mar.12, 2019, the disclosure of which is incorporated by reference herein.Still other suitable forms that distal end (32) may take will beapparent to those of ordinary skill in the art in view of the teachingsherein. Needle (30) of the present example comprises a metallic (e.g.,nitinol, stainless steel, etc.) hypodermic needle that is sized todeliver the therapeutic agent while being small enough to createself-sealing wounds as needle (30) penetrates tissue structures of thepatient's eye, as will be described in greater detail below. By way ofexample only, needle (30) may be 35 gauge with a 100 μm inner diameter,although other suitable sizes may be used. For instance, the outerdiameter of needle (30) may fall within the range of 27 gauge to 45gauge; or more particularly within the range of 30 gauge to 42 gauge; ormore particularly within the range of 32 gauge to 39 gauge. As anothermerely illustrative example, the inner diameter of needle (30) may fallwithin the range of approximately 50 μm to approximately 200 μm; or moreparticularly within the range of approximately 50 μm to approximately150 μm; or more particularly within the range of approximately 75 μm toapproximately 125 μm.

Referring back to FIGS. 1-2, body (40) is generally shaped as anelongate rectangle with a curved distal end. The particular shape ofbody (40) that is shown is configured to be grasped by an operator.Alternatively, body (40) may be mounted on a support device or roboticarm for ease of positioning instrument (10), as described in U.S. patentapplication Ser. No. 14/619,256, entitled “Method and Apparatus forSubretinal Administration of Therapeutic Agent,” filed Feb. 11, 2015,issued as U.S. Pat. No. 10,226,379 on Mar. 12, 2019, the disclosure ofwhich is incorporated by reference herein.

Actuation assembly (60) includes an actuation member (62) and a lockingmember (66). Locking member (66) is removably attachable to bodyengagement portion (50), between body (40) and actuation member (62). Aswill be described in greater detail below, locking member (66) fills aspace between body (40) and actuation member (62) to prevent actuationmember (62) from being advanced distally relative to body (40). However,locking member (66) can be removed to selectively permit actuationmember (62) to be advanced distally relative to body (40).

FIGS. 2-4 show an exemplary actuation of instrument (10). In particular,as can be seen in FIG. 2, needle (30) is initially retracted intocannula (20) and locking member (66) is positioned between body (40) andactuation member (62), thereby preventing advancement of actuationmember (62). With instrument (10) in this configuration, cannula (20)may be positioned within an eye of a patient as will be described ingreater detail below.

Once cannula (20) is positioned within an eye of a patient, an operatormay desire to advance needle (30) relative to cannula (20). To advanceneedle (30), an operator may first remove locking member (66) by pullinglocking member (66) away from instrument (10), as can be seen in FIG. 3.Once locking member (66) is removed, actuation member (62) may be movedor translated relative to body (40) to advance needle (30) relative tocannula (20) as described in U.S. patent application Ser. No.14/619,256, entitled “Method and Apparatus for Subretinal Administrationof Therapeutic Agent,” filed Feb. 11, 2015, issued as U.S. Pat. No.10,226,379 on Mar. 12, 2019, the disclosure of which is incorporated byreference herein. Actuation member (62) of the present example is onlyconfigured to translate needle (30) and not rotate needle (30). In otherexamples, it may be desirable to rotate needle (30). Accordingly,alternative examples may include features in actuation member (62) torotate and translate needle (30).

In the present example, advancement of actuation member (62) intocontact with body (40) as shown in FIG. 4 corresponds to advancement ofneedle (30) to a position relative to cannula (20) to a predeterminedamount of penetration within an eye of a patient. In other words,instrument (10) is configured such that an operator only has to advanceactuation member (62) into contact with body (40) to properly positionneedle (30) within an eye of a patient. In some examples, thepredetermined amount of advancement of needle (30) relative to cannula(20) is between approximately 0.25 mm to approximately 10 mm; or moreparticularly within the range of approximately 0.1 mm to approximately10 mm; or more particularly within the range of approximately 2 mm toapproximately 6 mm; or more particularly to approximately 4 mm. In otherexamples, contact between actuation member (62) and body (40) may haveno particular significance besides the maximum advancement of needle(30) relative to cannula (20). Instead, instrument (10) may be equippedwith certain tactile feedback features to indicate to an operator whenneedle (30) has been advanced to certain predetermined distancesrelative to cannula (20). Accordingly, an operator may determine thedesired depth of penetration of needle (30) into a patient's eye basedon direct visualization of indicia on instrument and/or based on tactilefeedback from instrument (10). Of course, such tactile feedback featuresmay be combined with the present example, as will be apparent to thoseof ordinary skill in the art in view of the teachings herein.

Actuation member (62) includes a lumen (not shown) extendinglongitudinally though actuation member (62). The lumen of actuationmember (62) is configured to receive supply tube (64). In particular,supply tube (64) connects to the fluid coupling member of bodyengagement portion (not shown), extends proximally through bodyengagement portion, proximally through actuation member (62), andproximally out through the proximal end of actuation member (62). Thus,supply tube (64) defines a conduit through actuation member (62) toneedle (30) such that fluid may be injected via supply tube (64) throughneedle (30) to an injection site. In the present example, the proximalend of supply tube (64) connects to a fluid source such as a syringe, anautomated or semi-automated injector, or any other suitable fluidsource. It should be understood that the proximal end of supply tube(64) may include a luer fitting and/or any other suitable kind offitting to enable supply tube (64) to be releasably coupled with a fluidsource.

II. Exemplary Alternative Instruments and Features

In some examples, it may be desirable to vary certain components orfeatures of the instruments described herein. For instance, it may bedesirable to utilize instruments similar to instrument (10) withalternative mechanisms to actuate needle (30). Yet in other examples, itmay be desirable to utilize instruments similar to instrument (10)equipped with different cannula (20) or needle (30) geometries.Instruments having the above referenced variations may be desirable fordifferent surgical procedures, or surgical procedures similar to theprocedure discussed above, to engage tissue structures having varyingphysical properties. While certain examples of variations are describedherein, it should be understood that the instruments described hereinmay include any other alternative features as will be apparent to thoseof ordinary skill in the art in view of the teachings herein.

FIG. 7 shows an exemplary alternative instrument (2010) that is similarto instrument (10) described above. While certain features andoperabilities of instrument (2010) are described below, it should beunderstood that, in addition to or in lieu of the following, instrument(2010) may be configured and/or operable in accordance with any of theteachings of U.S. patent application Ser. No. 14/619,256, entitled“Method and Apparatus for Suprachoroidal Subretinal Administration ofTherapeutic Agent,” filed Feb. 11, 2015, issued as U.S. Pat. No.10,226,379 on Mar. 12, 2019, the disclosure of which is incorporated byreference herein. Like with instrument (10), instrument (2010) of thepresent example is generally usable in the procedure described herein todeliver a therapeutic fluid subretinally to an eye of a patient from asuprachoroidal approach. It should therefore be understood thatinstrument (2010) may be readily used in place of instrument (10) toperform the medical procedures described herein. Like instrument (10),instrument (2010) of this example comprises a cannula (2020), a body(2040), and an actuation assembly (2100). Cannula (2020) includes anitinol needle (2030) extending therethrough and is substantially thesame as cannula (20) described above. In the present example, cannula(2020) and needle (2030) are substantially identical to cannula (20) andneedle (30) described above.

The primary difference between instrument (10) and instrument (2010) isthat actuation assembly (2100) of instrument (2010) is rotatable insteadof being slidable. Additionally, instrument (2010) includes a valveassembly (not shown) that is operable to change the fluid state ofneedle (2030) according to the configuration or position of arms (2232).Particularly, arms (2232) are actuatable among three positions wherebyneedle (2030) is in three different fluid states. In the first positionof arms (2232) shown in FIG. 7, valve assembly allows fluid to passthrough both first supply tube (2090) and second supply tube (2091) toneedle (2030). In a second position of arms (2232), valve assemblyallows fluid to pass through first supply tube (2090) to needle (2030),but prevents fluid from passing through second supply tube (2091) toneedle (2030). In a third position of arms (2232) valve assembly allowsfluid to pass through second supply tube (2091) to needle (2030) butprevents fluid from passing through first supply tube (2090) to needle(2030). In the present example, first supply tube (2090) is configuredto couple with a source of bleb fluid (340) (e.g., BSS); while secondsupply tube (2091) is configured to couple with a source of therapeuticagent (e.g., therapeutic agent (341)). It should be understood that eachfluid supply tube (2090, 2091) may include a conventional luer featureand/or other structures permitting fluid supply tubes (2090, 2091) to becoupled with respective fluid sources. Actuation assembly (2100) isgenerally operable to translate the valve assembly longitudinally tothereby translate needle (2030) longitudinally relative to cannula(2020) through rotation of a knob member (2110).

When actuation assembly (2100) is in the proximal position, an operatormay rotate knob member (2110) in either a counter clockwise or clockwisedirection. If knob member (2110) is rotated in the counter clockwisedirection, rotation member (2110) will merely rotate freely. To beginadvancement of actuation assembly (2100), the valve assembly, and needle(2030), an operator may rotate knob member (2110) in the clockwisedirection. Clockwise rotation of knob member (2110) will act totranslate knob member (2110) distally and will also act to translate thevalve assembly and needle (2030) distally. An operator may continueclockwise rotation of knob member (2110) to drive needle (2030) out ofthe distal end of cannula (2020). Once needle (2030) has been advancedto its furthest distal position relative to the distal end of cannula(2020), further clockwise rotation of knob member (2110) will merelyresult in free rotation of knob member (2110) due to slipping of clutchfeatures that are integrated into actuation assembly (2100). With needle(2030) in the distal position, the operator may actuate valve assemblyto enable the delivery of therapeutic agent via needle (2030) asdescribed in greater detail below.

After the therapeutic agent is delivered, the operator may then wish toretract needle (2030). Counter clockwise rotation of knob member (2110)will cause proximal translation of actuation assembly (2100), the valveassembly, and needle (2030) relative to body (2040). It should beunderstood that as actuation assembly (2100) is rotated to actuate thevalve assembly, and needle (2030), the valve assembly and needle (2030)remain substantially rotationally stationary relative to body (2040). Itshould also be understood that although rotation member (2110) of thepresent example is described as being manually rotated, rotation member(2110) may be rotated via a motor and/or some other motive source. Thus,it should be understood that translation of needle (2030) may bemechanically/electrically driven via a servomotor. The actuation of aservomotor may be controlled by a servo controller as will be describedin more detail below. Such a servo control may be manually operated.Additionally or alternatively, such a servo controller may be operatedvia a computer acting on feedback from instrument (2010) or any othercomponent described herein.

III. Exemplary Suture Measurement Template

FIG. 8 shows an exemplary suture measurement template (210) that may beused in a procedure providing subretinal delivery of a therapeutic agentfrom a suprachoroidal approach, as will be described in greater detailbelow. Generally, template (210) is configured to be pressed against aneye of a patient to stamp a particular pattern of pigment onto thepatient's eye. It should be understood that reference herein to pressingtemplate (210) against an eye of a patent may include, but is notnecessarily limited to, pressing template (210) directly against thesclera (304) surface (e.g., after the conjunctiva has been taken down orotherwise displaced). Template (210) comprises a rigid body (220) and arigid shaft (240). As will be described in greater detail below, body(220) is generally contoured to correspond to the curvature of apatient's eye such that body (220) may be pressed or placed onto atleast a portion of the patient's eye. Body (220) comprises an upperguide portion (222) and a plurality of protrusions (230) extendingdistally from an eye face (224) of body (220).

Upper guide portion (222) is generally semi-circular in shape and isdisposed at the top of body (220). The semi-circular shape of upperguide portion (222) has a radius that corresponds to the curvature ofthe limbus of a patient's eye. In other words, upper guide portion (222)curves proximally along a first radius corresponding to a radius ofcurvature of a patient's eyeball; and downwardly (toward thelongitudinal axis of shaft (240)) along a second radius corresponding toa radius of curvature of the limbus of the patient's eye. As will bedescribed in greater detail below, upper guide portion (222) may be usedto properly locate template (210) relative to the limbus of thepatient's eye. Accordingly, any pigmentation that may be deposited ontoa patient's eye by template may be positioned relative to the limbus ofthe patient's eye.

Protrusions (230) are spaced a predetermined distance from upper guideportion (222). In particular, protrusions (230) form a pattern that maycorrespond to relevant marks for use during the method described below.Protrusions (230) of the present example comprise four suture loopprotrusions (230 a-230 h) and two sclerotomy protrusions (230 i, 230 j).Suture loop protrusions (230 a-320 h) and sclerotomy protrusions (230 i,230 j) extend outwardly from body (220) an equal distance such thatprotrusions (230) collectively maintain the curvature defined by body(220). In other words, the tips of protrusions (230 a-230 j) all liealong a curved plane that is defined by a radius of curvaturecomplementing the radius of curvature of the patient's eyeball. The tipsof protrusions (230 a-230 j) are rounded and atraumatic such thatprotrusions (230 a-230 j) may be pressed against the eye withoutdamaging the sclera or other portions of the patient's eye.

Shaft (240) extends proximally from body (220). Shaft (240) isconfigured to permit an operator to grasp template (210) and manipulatebody (220). In the present example, shaft (240) is integral with body(220). In other examples, shaft (240) may be selectively attachable tobody by a mechanical fastening means such as a threaded coupling or amechanical snap fit, etc. In some versions, an operator may be presentedwith a kit comprising a shaft (240) and a plurality of bodies (220). Thebodies (220) may have different curvatures to correspond with differenteyeballs having different radii of curvature. The operator may thusselect an appropriate body (220) from the kit based on the anatomy ofthe particular patient before the operator; and the operator may thensecure the selected body (220) to the shaft (240). Although not shown,it should be understood that the proximal end of shaft (240) mayadditionally include a t-grip, knob, or other gripping feature to permitan operator to more readily grip shaft (240).

In an exemplary use, suture loop protrusions (232) and sclerotomyprotrusions (234) each correspond to a particular portion of the methoddescribed below. In particular, prior to, or during the method describedbelow, an operator may coat protrusions (230) with a biocompatiblepigment or ink by pressing protrusions (230) onto a pigment or ink pad(250), by brushing the pigment or ink onto protrusions (230), or byotherwise applying the pigment or ink to protrusions (230). Onceprotrusions (230) have received the pigment or ink, an operator may markan eye of a patent by pressing protrusions (230) of template (210) ontothe eye of the patient, as will be described in greater detail below.Once template (210) is removed from an eye of a patient, the pigmentfrom protrusions may remain adhered to the eye to mark particular pointsof interest, as will be described in greater detail below.

IV. Exemplary Method for Subretinal Delivery of Therapeutic Agent from aSuprachoroidal Approach

FIGS. 9A-11C show an exemplary procedure for subretinal delivery oftherapeutic agent from a suprachoroidal approach using instrument (10)described above. It should be understood however, that instrument (2010)may be readily used in addition to or in lieu of instrument (10) in theprocedure described below. By way of example only, the method describedherein may be employed to treat macular degeneration and/or other ocularconditions. Although the procedure described herein is discussed in thecontext of the treatment of age-related macular degeneration, it shouldbe understood that no such limitation is intended or implied. Forinstance, in some merely exemplary alternative procedures, the sametechniques described herein may be used to treat retinitis pigmentosa,diabetic retinopathy, and/or other ocular conditions. Additionally, itshould be understood that the procedure described herein may be used totreat either dry or wet age-related macular degeneration.

As can be seen in FIG. 9A, the procedure begins by an operatorimmobilizing tissue surrounding a patient's eye (301) (e.g., theeyelids) using a speculum (312), and/or any other instrument suitablefor immobilization. While is immobilization described herein withreference to tissue surrounding eye (301), it should be understood thateye (301) itself may remain free to move. Once the tissue surroundingeye (301) has been immobilized, an eye chandelier port (314) is insertedinto eye (301) to provide intraocular illumination when the interior ofeye (301) is viewed through the pupil. In the present example, eyechandelier port (314) is positioned in the inferior medial quadrant suchthat a superior temporal quadrant sclerotomy may be preformed. As can beseen in FIG. 10A, eye chandelier port (314) is positioned to directlight onto the interior of eye (314) to illuminate at least a portion ofthe retina (e.g., including at least a portion of the macula). As willbe understood, such illumination corresponds to an area of eye (301)that is being targeted for delivery of therapeutic agent. In the presentexample, only chandelier port (314) is inserted at this stage, withoutyet inserting an optical fiber (315) into port (314). In some otherversions, an optical fiber (315) may be inserted into chandelier port(314) at this stage. In either case, a microscope may optionally beutilized to visually inspect the eye to confirm proper positioning ofeye chandelier port (314) relative to the target site. In some examples,the target region may be identified by a relative lack of retinalpigmentation. Although FIG. 9A shows a particular positioning of eyechandelier port (314), it should be understood that eye chandelier port(314) may have any other positioning as will be apparent to those ofordinary skill in the art in view of the teachings herein.

Once eye chandelier port (314) has been positioned, the sclera (304) maybe accessed by dissecting the conjunctiva by incising a flap in theconjunctiva and pulling the flap posteriorly. After such a dissection iscompleted, the exposed surface (305) of the sclera (304) may optionallybe blanched using a cautery tool to minimize bleeding. Once conjunctivadissection is complete, the exposed surface (305) of the sclera (304)may optionally be dried using a WECK-CEL or other suitable absorbentdevice. Template (210), described above, may then be used to mark eye(301). As can be seen in FIG. 9B, template (210) is positioned to alignwith the limbus of eye (301). An operator may apply a light force totemplate (210) to apply pigment to eye (301). Template (210) is thenremoved, leaving pigment adhered to the exposed surface (305) of thesclera (304) to provide a visual guide (320) for an operator, as can beseen in FIG. 9C. An operator may then use visual guide (320) to attach asuture loop assembly (330) and to perform a sclerotomy. Visual guide(320) comprises a set of suture loop markers (321, 322, 323, 324, 325,326, 327) and a pair of sclerotomy markers (329).

FIG. 9D shows a completed suture loop assembly (330). As will bedescribed in greater detail below, suture loop assembly (330) isgenerally configured to guide cannula (20) of instrument (10) through asclerotomy and into eye (301). An exemplary procedure that may beemployed to create the suture loop assembly (330) that is shown in FIG.9D is described in U.S. patent application Ser. No. 14/619,256, entitled“Method and Apparatus for Subretinal Administration of TherapeuticAgent,” filed Feb. 11, 2015, issued as U.S. Pat. No. 10,226,379 on Mar.12, 2019, the disclosure of which is incorporated by reference herein.Once suture loop assembly (330) has been attached to eye (301), asclerotomy may be performed on eye (301). As seen in FIG. 9E, eye (301)is cut between sclerotomy markers (329) using a conventional scalpel(313) or other suitable cutting instrument. Although sclerotomy markers(329) are shown as comprising two discrete dots, it should be understoodthat in other examples, markers (329) may comprise any other type ofmarkings such as a solid, dotted or dashed line. The sclerotomyprocedure forms a small incision (316) through sclera (304) of eye(301). As can best be seen in FIG. 10B, the sclerotomy is preformed withparticular care to avoid penetration of the choroid (306). Thus, thesclerotomy procedure provides access to the space between sclera (304)and choroid (306). Once incision (316) is made in eye (301), a bluntdissection may optionally be performed to locally separate sclera (304)from choroid (306). Such a dissection may be performed using a smallblunt elongate instrument, as will be apparent to those of ordinaryskill in the art in view of the teachings herein.

With the sclerotomy procedure performed, an operator may insert cannula(20) of instrument (10) through incision (316) and into the spacebetween sclera (304) and choroid (306). As can be seen in FIG. 9F,cannula (20) is directed through guide loops (336) of suture loopassembly (330) and into incision (316). As described above, guide loops(336) may stabilize cannula (20). Additionally, guide loops (336)maintain cannula (20) in a generally tangential orientation relative toincision (316). Such tangential orientation may reduce trauma as cannula(20) is guided through incision (316) to stabilize cannula (20) and toprevent damage to surrounding tissue. As cannula (20) is inserted intoincision (316) through guide loops (336), an operator may use forceps orother instruments to further guide cannula (20) along an atraumaticpath. Of course, use of forceps or other instruments is merely optional,and may be omitted in some examples. Although not shown, it should beunderstood that in some examples cannula (20) may include one or moremarkers on the surface of cannula (20) to indicate various depths ofinsertion. While merely optional, such markers may be desirable to aidan operator in identifying the proper depth of insertion as cannula (20)is guided along an atraumatic path. For instance, the operator mayvisually observe the position of such markers in relation to guide loops(336) and/or in relation to incision (316) as an indication of the depthto which cannula (20) is inserted in eye (301). By way of example only,one such marker may correspond to an approximately 6 mm depth ofinsertion of cannula (20).

Once cannula (20) is at least partially inserted into eye (301), anoperator may insert an optical fiber (315) into eye chandelier port(314) the fiber (315) had not yet been inserted at this stage. With eyechandelier port (314) in place and assembled with optical fiber (315),an operator may activate eye chandelier port (314) by directing lightthrough optical fiber (315) to provide illumination of eye (301) andthereby visualize the interior of eye (301). Further adjustments to thepositioning of cannula (20) may optionally be made at this point toensure proper positioning relative to the area of geographic atrophy ofretina (308). In some instances, the operator may wish to rotate the eye(301), such as by pulling on sutures (334, 339), to direct the pupil ofthe eye (301) toward the operator in order to optimize visualization ofthe interior of the eye (301) via the pupil.

FIGS. 9G and 10C-10D show cannula (20) as it is guided between sclera(304) and choroid (306) to the delivery site for the therapeutic agent.In the present example, the delivery site corresponds to a generallyposterior region of eye (301) adjacent to an area of geographic atrophyof retina (308). In particular, the delivery site of the present exampleis superior to the macula, in the potential space between theneurosensory retina and the retinal pigment epithelium layer. FIG. 9Gshows eye (301) under direct visualization through a microscope directedthrough the pupil of eye (301), with illumination provided through fiber(315) and port (314). As can be seen, cannula (20) is at least partiallyvisible through a retina (308) and choroid (306) of eye (301). Thus, anoperator may track cannula (20) as it is advanced through eye (301) fromthe position shown in FIG. 10C to the position shown in 10D. Suchtracking may be enhanced in versions where an optical fiber (34) is usedto emit visible light through the distal end of cannula (20).

Once cannula (20) has been advanced to the delivery site as shown inFIG. 10D, an operator may advance needle (30) of instrument (10) asdescribed above with respect to FIGS. 3-4. As can be seen in FIGS.9H-9I, 10E, and 11A, needle (30) is advanced relative to cannula (20)such that needle (30) pierces through choroid (306) without penetratingretina (308). Immediately prior to penetrating choroid (306), needle(30) may appear under direct visualization as “tenting” the surface ofchoroid (306), as can be seen in FIG. 9H. In other words, needle (30)may deform choroid (306) by pushing upwardly on choroid, providing anappearance similar to a tent pole deforming the roof of a tent. Such avisual phenomenon may be used by an operator to identify whether choroid(306) is about to be pierced and the location of any eventual piercing.The particular amount of needle (30) advancement sufficient to initiate“tenting” and subsequent piercing of choroid (306) may be of anysuitable amount as may be determined by a number of factors such as, butnot limited to, general patient anatomy, local patient anatomy, operatorpreference, and/or other factors. As described above, a merely exemplaryrange of needle (30) advancement may be between approximately 0.25 mmand approximately 10 mm; or more particularly between approximately 2 mmand approximately 6 mm.

In the present example, after the operator has confirmed that needle(30) has been properly advanced by visualizing the tenting effectdescribed above, the operator infuses a balanced salt solution (BSS) orother similar solution as needle (30) is advanced relative to cannula(20). Such a BSS solution may form a leading bleb (340) ahead of needle(30) as needle (30) is advanced through choroid (306). Leading bleb(340) may be desirable for two reasons. First, as shown in FIGS. 9I,10F, and 11B, leading bleb (340) may provide a further visual indicatorto an operator to indicate when needle (30) is properly positioned atthe delivery site. Second, leading bleb (340) may provide a barrierbetween needle (30) and retina (308) once needle (30) has penetratedchoroid (306). Such a barrier may push the retinal wall outwardly (as isbest seen in FIGS. 10F and 11B), thereby minimizing the risk of retinalperforation as needle (30) is advanced to the delivery site. In someversions, a foot pedal is actuated in order to drive leading bleb (340)out from needle (30). Alternatively, other suitable features that may beused to drive leading bleb (340) out from needle (30) will be apparentto those of ordinary skill in the art in view of the teachings herein.

Once the operator visualizes leading bleb (340), the operator may ceaseinfusion of BSS, leaving a pocket of fluid as can be seen in FIGS. 9I,10F, and 11B. Next, a therapeutic agent (341) may be infused byactuating a syringe or other fluid delivery device as described abovewith respect to instrument (10). The particular therapeutic agent (341)delivered may be any suitable therapeutic agent configured to treat anocular condition. Some merely exemplary suitable therapeutic agents mayinclude, but are not necessarily limited to, drugs having smaller orlarge molecules, therapeutic cell solutions, certain gene therapysolutions, and/or any other suitable therapeutic agent as will beapparent to those of ordinary skill in the art in view of the teachingsherein. By way of example only, the therapeutic agent (341) may beprovided in accordance with at least some of the teachings of U.S. Pat.No. 7,413,734, entitled “Treatment of Retinitis Pigmentosa with HumanUmbilical Cord Cells,” issued Aug. 19, 2008, the disclosure of which isincorporated by reference herein.

In the present example, the amount of therapeutic agent (341) that isultimately delivered to the delivery site is approximately 50 μL,although any other suitable amount may be delivered. In some versions, afoot pedal is actuated in order to drive agent (341) out from needle(30). Alternatively, other suitable features that may be used to driveagent (341) out from needle (30) will be apparent to those of ordinaryskill in the art in view of the teachings herein. Delivery oftherapeutic agent may be visualized by an expansion of the pocket offluid as can be seen in FIGS. 9J, 10G, and 11C. As shown, therapeuticagent (341) essentially mixes with the fluid of leading bleb (340) astherapeutic agent (341) is injected into the suprachoroidal space.

Once delivery is complete, needle (20) may be retracted by slidingactuation assembly (60) proximally relative to body (40); and cannula(30) may then be withdrawn from eye (301). It should be understood thatbecause of the size of needle (20), the site where needle (20)penetrated through choroid (306) is self sealing, such that no furthersteps need be taken to seal the delivery site through choroid (306).Suture loop assembly (330) and chandelier (314) may be removed, andincision (316) in the sclera (304) may be closed using any suitableconventional techniques.

As noted above, the foregoing procedure may be carried out to treat apatient having macular degeneration. In some such instances, thetherapeutic agent (341) that is delivered by needle (20) may comprisecells that are derived from postpartum umbilicus and placenta. As notedabove, and by way of example only, the therapeutic agent (341) may beprovided in accordance with at least some of the teachings of U.S. Pat.No. 7,413,734, entitled “Treatment of Retinitis Pigmentosa with HumanUmbilical Cord Cells,” issued Aug. 19, 2008, the disclosure of which isincorporated by reference herein. Alternatively, needle (20) may be usedto deliver any other suitable substance or substances, in addition to orin lieu of those described in U.S. Pat. No. 7,413,734 and/or elsewhereherein. By way of example only, therapeutic agent (341) may comprisevarious kinds of drugs including but not limited to small molecules,large molecules, cells, and/or gene therapies. It should also beunderstood that macular degeneration is just one merely illustrativeexample of a condition that may be treated through the proceduredescribed herein. Other biological conditions that may be addressedusing the instruments and procedures described herein will be apparentto those of ordinary skill in the art.

V. Exemplary Manual Injection System with Spacer for ControllingDelivered Fluid Volume

When providing the delivery of fluid to the subretinal space asdescribed above, it may be desirable to use a fluid delivery instrumentthat delivers the fluid in a precise manner. This would include fullypurging all air from the fluid delivery system and ensuring that aprecise amount of fluid is delivered on a consistent basis. This mayeliminate the need for the physician to rely on their own judgment orskills to ensure that an appropriate amount of fluid is preciselydelivered on a consistent basis. Otherwise, it may be particularlydifficult for the physician to rely on their own judgment or skills whena relatively small amount of fluid needs to be delivered to thesubretinal space, where delivery of too much fluid may have an adverseeffect on the patient.

FIGS. 12A-15B show some components of a system that may be used to storeand deliver predetermined amount of fluids, such as bleb (340) fluid andtherapeutic agent (341) fluid as described above, to a subretinal spacein a precise and consistent manner via an instrument (e.g., instrument(10, 2010)). As discussed in more detail below, this system may befluidly coupled with an instrument (1000), which may be configured andoperable just like instrument (10, 2010) described above. Alternatively,instrument (1000) may take any other suitable form. As shown, the systemof the present example includes a syringe (402) and a measurement tab(404) that is configured to engage syringe (402) and act as a stop orspacer to prevent a syringe plunger assembly (406) from advancing past aparticular position relative to a syringe barrel (408).

As shown in FIGS. 12A-14B, syringe (402) of the present examplecomprises barrel (408) having a distal end (410) and a proximal end(412). Distal end (410) includes a first, dispensing opening (414) and athreaded portion (416) that enables coupling of the syringe (402) to aneedle, tubing, etc. In some versions, threaded portion (416) comprisesa conventional luer fitting. Proximal end (412) includes a secondopening (418) that is configured to receive syringe plunger assembly(406). Lumen (420) extends between the first and second openings (414,418) and includes a first portion that is configured to receive thesyringe piston (434) and plunger rod (436), and a second, decreasedcross-sectional dimension portion at the proximal end (412).

Proximal end (412) of syringe barrel (408) comprises a flange (422) thatextends radially outwardly relative to a longitudinal axis (424) ofsyringe (402) and acts as a finger grip when a user holds syringe (402).As shown best in FIGS. 15A-15B, flange (422) includes two parallelopposing flat edges (426 a, 426 b) and two opposing curved edges (428 a,428 b) that each extend between the flat edges (426 a, 426 b). Curvededges (428 a, 428 b) extend around axis (424). Flange (422) furtherincludes a proximal side (430) facing away from barrel (408) and adistal side (432) facing toward barrel (408).

As best seen in FIGS. 13B and 14A, plunger assembly (406) of the presentexample comprises a piston (434) and a plunger rod (436) that includes athumb flange (438) and a shaft (440). In the present example, piston(434) and plunger rod (436) are removably coupled to one another. Moreparticularly, plunger rod (436) includes a threaded portion (442), andpiston (434) includes a threaded portion (444) that is configured toreceive and threadably engage threaded portion (442) of plunger rod(436). Thus, piston (434) may be advanced and retracted within lumen(420) by advancing and retracting plunger rod (436) when piston (434) iscoupled thereto. Alternatively, as discussed in more detail below, whenplunger rod (436) is no longer coupled to piston (434), piston (434) maybe advanced and retracted by fluidly coupling lumen (420) with a sourceof pressurized air, as discussed in further detail below.

As shown best in FIGS. 15A-15B, a portion of shaft (440) includes across-section defined by equal length perpendicular members that crossat their midpoints (i.e., like a “+” sign), such that shaft (440)defines a first arm (446 a), a second arm (446 b) opposing the first arm(446 a), a third arm (446 c) extending perpendicular to the first andsecond arms (446 a-b), and a fourth arm (446 d) opposing the third arm(446 c) and extending perpendicular to the first and second arms (446a-b).

As shown best in FIGS. 12A-12C, 14A, and 15A-15B, tab (404) includes agrip portion (450) that extends along an imaginary plane (448) (FIG.15A) and that is configured to be grasped by an operator. Tab (404)further includes an engagement portion (452) that is configured toreleasably engage shaft (440) of syringe (402). In the present example,engagement portion (452) includes a first side (454), a second side(456), and a recess (458) defined between the first and second sides(454, 456). As shown, at least a portion of recess (458) defines a shapethat complements at least a portion of the shape of the shaft (440),such that recess (458) is configured to receive at least a portion ofshaft (440). Particularly, recess (458) defines part of a cross shapehaving a first recessed portion (460) that extends perpendicularly toplane (448); and a second recessed portion (462) that extendsperpendicularly from the first recessed portion (460) toward handle(450) and along plane (448). Engagement portion (452) defines a firstlip (464) on the first side (454) extending inwardly toward plane (448)and a second lip (466) on second side (456) extending inwardly towardsplane (448). Tab (404) further includes an upper flange (468) and lowerflange (470) on each end of the handle (450). Flanges (468, 470) eachextend along planes that are parallel to each other and that areperpendicular to plane (448). Various other suitable ways in which tab(404) may be configured will be apparent to a person skilled in the artin view of the teachings herein.

In order to direct tab (404) into engagement with shaft (440), anoperator may grasp handle (450) and direct engagement portion (452)toward shaft (440). Lips (464, 466) initially contact the third andfourth arms (446 c, 446 d) of shaft (440), respectively and cause thefirst and second sides (454, 456) of tab to flex away from one anothersuch that each side (454, 456) flexes outwardly away from plane (448).Eventually, lips (464, 466) cam back along third and fourth arms (446 c,446 d) such that the first and second sides (454, 456) move backinwardly toward plane (448). Lips (464, 466) and first recessed portion(460) receive third and fourth arms (446 c, 446 d) and second recessedportion (462) receives first arm (446 a). Tab (404) thus provides areleasable snap fit with shaft (440) in the present example. Of course,tab (404) may be directed into engagement with shaft (440) such thatengagement portion (452) engages shaft (440) in a different manner(458), e.g., such that engagement portion (452) engages a different setof arms (444 a-d). Other suitable ways in which tab (404) may coupleshaft (440) will be apparent to persons skilled in the art in view ofthe teachings herein.

In the present example, once tab (404) engages shaft (440), the operatormay adjust tab (404) such that the bottom flange (470) abuts flange(422) of syringe (402). Alternatively, the operator may place tab (404)into engagement with shaft (440) such that upper flange (468) of tabgenerally abuts thumb flange (438). As another merely illustrativeexample, the operator may place tab (404) into engagement with shaft(440) at an intermediate position along shaft between flange (422) andthumb flange (438). In the present example, tab (404) is configured toengage shaft (440) in a manner that allows tab to slide relative toshaft (440) and that allows shaft (440) to slide relative to tab (404).Tab (404) is further configured such that when the plunger rod (436) isadvanced relative to barrel (408), thumb flange (438) is prevented fromadvancing further when thumb press (436) abuts upper flange (468) andlower flange (470) abuts flange (422) of syringe (402). Tab (404) thusrestricts distal advancement of plunger assembly (406) relative tobarrel (408).

In the example where the initial position of tab (404) is such thatlower flange (470) of tab (404) abuts flange (422) of syringe (402),thumb flange (438) eventually bottoms out against upper flange (468) oftab (404) as plunger assembly (408) is advanced distally relative tobarrel (408). In the example where the initial position of tab (404) issuch that the upper flange (468) of tab (404) abuts thumb flange (438),lower flange of tab (404) eventually bottoms out against flange (422) ofsyringe (402) as plunger assembly (406) is advanced distally relative tobarrel (408). In the example where the initial position of tab (404) issuch that tab (404) is placed in an intermediate position between thumbflange (438) and flange (422) of syringe (402), tab (404) initiallymoves with shaft (440) as shaft (440) is advanced distally until lowerflange (470) of tab (404) abuts flange (422) of syringe (402). As theoperator continues to advance the syringe (402), thumb flange (438)bottoms out against upper flange (468) of tab (404). Regardless of theinitial engagement position of tab (404) relative to shaft (440), in thepresent example, tab (404) may be sized and configured to ensure that apredetermined amount of fluid (472) remains in syringe (402) onceplunger is advanced relative to tab (404) such that thumb flange (438)abuts upper flange of tab (404), and lower flange of tab (404) abutsflange of syringe (402).

Tab (404) may be removed from engagement with shaft (440) by, forexample, the operator pulling tab (404) away from shaft along a paththat is transverse to the longitudinal axis of shaft (440), with asufficient force to overcome the engagement between engagement portion(452) and shaft (440). Absent the force, engagement portion (440) isconfigured to maintain the engagement between tab (404) and shaft (440).Upon being subjected to such a removal force, however, in the presentexample, lips (464, 466) cam against third and fourth arms (446 c, 446d), respectively, and first and second sides (454, 456) are urged awayfrom plane (448). As the operator continues to move tab (404) away fromshaft (440), lips (464, 466) eventually disengage from third and fourtharms (446 c, 446 d), and first and second sides (454, 456) flex backinwardly toward plane (448) and toward one another. In some alternativeexamples, tab (404) includes features that may be manipulated tofacilitate release of shaft (440) by engagement portion (452). Forinstance, tab (404) may include features that the operator pinchestoward each other in order to make engagement portion immediatelyrelease engagement portion (452). Various suitable features that may beincorporated into tab (404) in order to facilitate release of shaft(440) by engagement portion (452) will be apparent to those of ordinaryskill in the art in view of the teachings herein.

In an exemplary use as shown in FIG. 12A, an operator may couple barrel(404) with a fluid source (474) and then draw fluid into syringe (402)from fluid source (474) by retracting plunger rod assembly (406)relative to barrel (408) (e.g. manually or mechanically). The operatormay then secure tab (404) to shaft (440) and decouple fluid source (474)from syringe (402) as shown in FIG. 12B. While tab (404) is secured toshaft (440) after fluid is drawn into syringe (402) in this example, itshould be understood that tab (404) may alternatively be engaged withshaft (440) before fluid is drawn into syringe (402) or while fluid isbeing drawn into syringe (402).

Once fluid has been drawn into syringe (402), fluid source (474) hasbeen decoupled from syringe, and tab (404) has been secured to shaft(440), the operator may push plunger assembly (406) distally relative tobarrel (408). For at least a first part of this advancement, theoperator may orient syringe (402) upwardly such that any air in lumen(420) will be positioned at distal end (410). Thus, piston (434) willfirst purge the air out of the space in lumen (420) defined betweenpiston (434) and distal end (410) as plunger assembly (406) is distallyadvanced through a first range of motion. As the operator continues toadvance plunger assembly (406), some fluid may be ejected out throughopening (414). Plunger assembly (406) will eventually reach the stateshown in FIG. 12C, where tab (404) is engaged with both flange (422) ofsyringe (402) and thumb flange (438) of plunger rod (436). Tab (404)thus arrests further advancement of plunger assembly (406) relative tobarrel (408) at this stage. It should be understood that this willconsistently result in a fixed, predetermined amount of fluid in barrel(408). The amount of fluid will be based on the separation distancebetween flanges (468, 470).

As also shown in FIG. 12C, once thumb flange (438) has bottomed outagainst tab (404), the operator may couple distal end (410) with a fluiddelivery instrument (1000) via any suitable conduit (e.g., flexibletube, etc.). By way of example only, instrument (1000) may beconstructed and operable just like either instrument (10, 2010)described above. It should therefore be understood that syringe (402)and plunger assembly (406) may be used to deliver bleb (340) and/ortherapeutic agent (341) fluid as described above. Alternatively,instrument (1000) may have any other suitable configuration and may beconfigured for use in any suitable procedure calling for delivery of apredetermined amount of fluid. It should also be understood that syringe(402) and plunger assembly (406) may be used to deliver any suitablekind of fluid. Various suitable fluids, instruments, and medicalprocedures that may be associated with syringe (402), plunger assembly(406), and tab (404) will be apparent to those of ordinary skill in theart in view of the teaching herein.

After reaching the state shown in FIG. 12C, once instrument (1000) ispositioned for delivery of fluid at an appropriate location, theoperator may remove tab (404) from shaft (440) as shown in FIG. 12D. Theoperator may remove tab (404) from shaft (440) by grasping grip (450)and thereby pulling on tab (404) with a force sufficient to disengageengagement portion (452) from shaft (440), as discussed above. Tab (404)may remain on shaft (440) up until instrument (1000) has reached theappropriate location for fluid delivery. In some alternative versions,tab (404) is removed from shaft (440) before distal end (410) is coupledwith instrument (1000). Once tab (404) is removed from shaft (440), theoperator may advance plunger assembly (406) fully distally until thumbflange (438) bottoms out against flange (422) as shown in FIG. 12E. Atthis stage, piston (434) has been pressed to the distal end of lumen(420) such that the entire predetermined volume will have been expelledthrough distal end (410) to instrument (1000).

VI. Exemplary Adapters for Syringes to Couple with Powered InjectionSystem

In some instances, it may be desirable to use one or more poweredcomponents (e.g., a pump, etc.) to deliver bleb fluid (340), therapeuticagent (341), etc., instead of relying on the operator to deliver suchfluid manually by pressing on plunger assembly (406). It may thereforebe desirable to modify syringe (402) to enable the modified version ofsyringe (402) to be used in a system that uses one or more poweredcomponents (e.g., a pump, etc.) to deliver bleb fluid (340), therapeuticagent (341), etc.

FIGS. 13A-14B show an exemplary alternative method of using syringe(402) and plunger assembly (406), to prepare syringe (402) for use in asystem with one or more powered components as described in greaterdetail below. This method is substantially similar to the methoddescribed above with respect to FIGS. 12A-12E. The method shown in FIGS.13A-14B begins at after reaching the stage shown in FIG. 12C anddescribed above, where plunger assembly (406) has reached apredetermined depth of advancement into syringe (402), as governed bytab (404), resulting in a predetermined volume of fluid in syringe(402). While not shown in FIGS. 13A-14B, it should be understood thatinstrument (1000) may be coupled with distal end (410) of syringe (402)during the stages shown in FIGS. 13A-14B. In the present example,instead of the operator advancing plunger assembly (406) furtherdistally in order to expel the fluid from syringe (402), the operatordecouples rod (440) from piston (434) by rotating rod (440) to unscrewthreaded portion (442) from threaded portion (444). Once rod (440) hasbeen decoupled from piston (434), the operator may fully remove rod(440) from syringe (402) as shown in FIGS. 13B-13C and 14B, then set rod(440) aside. Piston (434) will remain in place in barrel (408), as shownin FIG. 14B. With piston (434) being positioned deeply within lumen(420), barrel (408) may protect piston (434) from inadvertent engagementwith other objects, such that piston (434) may remain in the sameposition within barrel (408) until piston (434) is acted upon by apressurized medium as will be described in greater detail below. Withpiston (434) remaining in the same position within barrel (408), thesame predetermined amount of fluid may also remain within barrel (408).

FIGS. 20A-21C show how an adapter (502) and a collar (504) may besecured to syringe (402) to form an assembly (500). Adapter (502)enables syringe (402) to be coupled with a system with one or morepowered components as described in greater detail below. FIGS. 16-17show adapter (502) in greater detail. Adapter (502) may be coupled withproximal end (412) of syringe (402) after syringe (402) reaches thestate shown in FIGS. 13C and 14B. Adapter (502) of this example has aproximal end (506) and a distal end (510). Proximal end (506) has abarbed connection feature (508) that is adapted for connection totubing, for example. Distal end (510) comprises a tubular member (512)having annular recesses (514). A lumen (516) extends between a firstopening (518) at proximal end (506) and a second opening (520) at distalend (510). A flange (522) is disposed between proximal end (506) anddistal end (510) of syringe adapter (502). Flange (522) includes aproximal side (524) facing proximal end (506) of syringe adapter (502)and a distal side (526) facing distal end (510). Flange (522) includes apair of opposing curved edges (528 a, 528 b) and a pair of opposingstraight edges (530 a, 530 b). Each straight edge (530, 530 b) isdisposed between opposing ends of the curved edges (528 a, 528 b). Inthe present example, syringe adapter (502) is a single unitary body, butin other examples may comprise multiple portions coupled together.Various other suitable ways in which syringe adapter (502) may beconfigured will be apparent to a person skilled in the art in view ofthe teachings herein.

As shown best in FIGS. 17 and 21A-C, annular recesses (514) each receivesealing elements, which in the present example include an O-ring (532)received in each of the annular recesses (514). Tubular member (512) issized and configured to be received in second opening (418) of syringebarrel (408) once, for example, plunger rod (436) is decoupled frompiston (434) as shown in FIGS. 13C and 14B. O-rings (532) are configuredto provide a fluid tight seal between lumen (420) of syringe (402) andsyringe adapter (502) to prevent the escape of fluid pressure fromsecond end of syringe (402). As discussed in more detail below, proximalend (506) of syringe adapter (502) may be coupled to a source ofpressurized air or other fluid and distal end (510) of syringe adapter(502) may be received in second end of syringe (402). Therefore,pressurized air or fluid may be communicated to lumen (420) of syringe(402) via adapter (502), proximal to piston (434), and cause theadvancement of piston (434) within syringe (402) to thereby dispensefluid from syringe (402). In some instances, adapter (502) may be usedto communicate suction to lumen (420) of syringe (402), proximal topiston (434), and cause the retraction of piston (434) within syringe(402) to thereby draw fluid into syringe (402).

FIGS. 18-19 show collar (504) in greater detail. Collar (504) may beused to secure adapter (502) to proximal end (412) of syringe (402) andthereby prevent movement of adapter (502) relative to syringe (402).Collar (504) is configured to keep adapter (502) secured to syringe(412) even when adapter (502) is communicating a pressurized medium tosyringe (402) at a fluid pressure between approximately 20 psi andapproximately 40 psi. Collar (504) of the present example includes agenerally U-shaped body defined by a U-shaped wall (532), a first, upperflange (534) extending perpendicularly from the wall (532) and anopposing second, lower flange (536) extending perpendicularly from thewall (532). There is a curved, filleted edge (538, 540) between the wall(532) and each of the first and second flanges (534, 536), respectively.First flange (534) includes a U-shaped inner edge (542) with opposingstraight portions (544 a, 544 b) and a curved portion (546) between thestraight portions (544 a, 544 b). Second flange (536) also includes aninner edge (548) with opposing straight portions (550 a, 550 b) and acurved portion (552) between the straight portions (550 a, 550 b). Firstflange (534) and second flange (536) each include a respective innerportion (554, 556). Wall (532) includes an inner wall portion (558) thatextends between and perpendicularly to inner flange portions (554, 556).Thus, inner flange portions (554, 556) and inner wall portion (558)define a U-shaped cavity.

Inner portion (554) of first flange (534) includes a plurality of ramps(560 a-c) extending toward inner portion (556) of second flange (536),while inner portion (556) of second flange (536) includes a plurality oframps (562 a-c) extending toward inner portion (554) of first flange(534). Each of the ramps (560 a-c, 562 a-c) extends parallel to edges(544 a-b, 550 a-b). Ramps (560 a, 560 c) extend from near a frontportion of collar (502) along opposing sides of inner portion (554) offlange (534) toward a rear portion of collar, while ramps (562 a, 562 c)extend from near a front portion of collar (502) along inner portion(556) of flange (536) toward a rear portion of collar (502). Ramp (560b) extends along inner portion (554) from near curved edge (546) towardrear portion of collar. Similarly, ramp (562 b) extends along innerportion (556) from near curved edge (552) towards rear portion of collar(502). Ramps (560 a-c) include tapered leading portions (564 a-c),respectively. Similarly, ramps (562 a-c) include tapered leadingportions (566 a-c), respectively.

FIGS. 20A-21C show how syringe (502), adapter (502), and collar (504)may be assembled together to form an assembly (500). It should beunderstood that the process described below would begin after syringe(502) has reached the state shown in FIGS. 13C and 14B. In order toassemble assembly (500), the operator directs tubular member (512) ofsyringe adapter (502) into opening (418) of syringe (402), in theabsence of plunger rod (436), such that flange (522) of syringe adapter(502) is adjacent to or generally abuts flange (422) of syringe (402).This results in a transition from the configuration shown in FIGS. 20Aand 21A to the configuration shown in FIGS. 20B and 21B. In the presentexample, O-rings (532) are sized and configured such that they arecompressed to a smaller cross-sectional dimension between annularrecesses (514) and lumen (420). O-rings (532) of the present example mayinclude a lubricious coating such as silicone in order to reduce thefriction between O-rings (532) and wall (420) during insertion ofsyringe adapter (502) into syringe (402).

The operator may then direct engagement collar (502) into engagementwith syringe (402) and syringe adapter (502), as shown in FIGS. 20C and21C. In the present example, the operator directs engagement collar(502) relative to syringe (402) and syringe adapter (502) such that aportion of flanges (422, 522) enter into the U-shaped cavity.Particularly, engagement collar (502) is received within the U-shapedcavity such that curved edges of flanges (428 a, 528 a) and flanges (430a, 530 a) are received adjacent to opposing inner wall portions (558) ofengagement collar (502). As flanges (422, 522) are directed into theU-shaped cavity, proximal side (524) of flange (522) rides againsttapered portions (564 a, 564 c) of ramps (560 a, 560 c), respectively,and distal side (432) of flange (422) rides against tapered portions(566 a, 566 c) of ramps (562 a, 562 c), respectively. As engagementcollar (504) is directed further into engagement with syringe adapter(502) and syringe (402), flange (522) rides along non-tapered portionsof ramps (560 a, 560 c) and flange (422) rides along non-taperedportions of ramps (462 a, 462 c). Thus, as the distance between ramps(460 a, 462 a) and ramps (460 c, 462 c) decreases to a generallyconstant distance past their respective tapered portions (564 a, 566 a)and (564 c, 566 c), compressive force from ramps (560 a, 562 a) becomesgreater and flanges (422, 522) may be urged closer together such thatdistal side (526) of flange (522) more closely abuts and is urged in acompressive manner against proximal side (430) of flange (422).

Eventually, straight edge (462 a) of flange (422) and straight edge (530a) of flange (522) are brought into contact with and ride againstleading tapered portions of ramps (564 b, 566 b), respectively; and ridealong to the non-tapered portions of ramps (560 b, 562 b). Ramps (560a-c) and ramps (562 a-c) of the present example are rigid such that theinteraction between ramps (560 a-c), ramps (562 a-c), and flanges (422,522) results in an interference fit configuration of assembly (500).Ramps (560 a-c), ramps (562 a-c) and/or flanges (422, 522) may includeother features that increase the frictional force therebetween and/orthat increase the compressive force on flanges (422, 522) from ramps(560 a-c, 562 a-c). Suitable other ways in which assembly (500) may beconfigured and assembled will be apparent to persons skilled in the artin view of the teachings herein.

After reaching the state shown in FIGS. 20C and 21C, the operator maycouple a flexible tube with barbed connection feature (508) to therebycouple assembly (500) with a source of a pressurized medium (e.g., air,saline) in a system with one or more powered components as described ingreater detail below. The operator may further couple threaded portion(416) of syringe (402) with instrument (1000) to thereby dispense thefluid from syringe (402) to instrument (1000) as also described below.

FIGS. 23-27C show another exemplary assembly (600) including a syringe(602), a syringe adapter (702), and an engagement collar (804). Assembly(600) may also be coupled with a system with one or more poweredcomponents as described in greater detail below. In some examples,assembly (600) may also include a tab, such as tab (404). Assembly (600)is configured to operate substantially similar to assembly (500) suchthat syringe adapter (702) is configured to enable syringe (602) to becoupled to tubing, etc., that is further coupled to a source of apressurized fluid medium. Similarly, engagement collar (804) isconfigured secure syringe (602) to syringe adapter (702) and to assistin preventing the escape of pressurized fluid from syringe (602) and/orsyringe adapter (702). In that regard, syringe (602) is configured tooperate substantially similar to syringe (402), except for thedifferences discussed below. Syringe adapter (702) is configured tooperate substantially similar to syringe adapter (502), except for thedifferences discussed below. Similarly, engagement collar (804) isconfigured to operate substantially similar to engagement collar (504),except for the differences discussed below.

Syringe (602) of the present example comprises barrel (608) having adistal end (610) and a proximal end (612)). Distal end (610) includes afirst, dispensing opening (614) and a threaded portion (616) thatenables coupling of the syringe (602) to a needle, tubing, etc. In someversions, threaded portion (616) comprises a conventional luer fitting.Proximal end (612) includes a second opening (618) that is configured toreceive tubular member (640). Lumen (620) extends between first andsecond openings (614, 618).

Proximal end (612) of syringe barrel (608) further comprises a flange(622), which extends radially outwardly relative to a longitudinal axis(624) of syringe (602) and acts as a finger grip when a user holdssyringe (602). As shown best in FIGS. 22 and 26A, flange (622) isgenerally hexagonally shaped in the present example, though it should beunderstood that any other suitable shape may be used. Flange (622)further includes a proximal side (630) facing away from barrel (608) anda distal side (632) facing toward barrel (608).

Syringe (612) further includes a tubular member (640) received withinlumen (620). Tubular member (640) includes a first end (642) having afirst opening (644) abutted with the distal end of lumen (620) adjacentto dispensing opening (614) and a second end (646) having a secondopening (648). Tubular member (640) includes a lumen (650) extendingbetween first and second ends (646, 648). Tubular member (640) isfrictionally received within lumen of syringe (602). A tube (652)extends distally from lumen (650) of tubular member (640), throughsecond opening (648) of tubular member (640), and out dispensing opening(614) of syringe (602). Tubular member (640) is configured to receive aplunger assembly, such as plunger assembly (406), in order to draw fluidinto lumen (650) of tubular member (640) and prime syringe (602).Similar to syringe (402), plunger assembly (406) may be used to dispensefluid from syringe (606). Alternatively, plunger assembly (406) may bedecoupled, leaving a piston, such as piston (434), within lumen (450) sothat piston (434) may be advanced and retracted via fluid pressure, inthe manner discussed above with respect to syringe (402).

As shown best in FIGS. 24-25, syringe adapter (702) of the presentexample includes a proximal tubular portion (706) extending along axis(707) and comprising a barbed connection feature (708) that is adaptedfor connecting proximal tubular portion (706) to tubing, for example.Syringe adapter (702) further includes a distal tubular portion (710)opposing proximal tubular portion (706). Distal tubular portion (710)has a greater cross-sectional dimension than proximal tubular portion(706) and includes a plurality of annular recesses (714). A lumen (716)extends between a proximal opening (718) at proximal portion (706) and adistal opening (720) at distal portion (710).

Syringe adapter (702) further comprises a flange (722) positioned adistance away from distal tubular portion (710) (in the direction ofarrow (713)). Flange (722) is positioned coaxially relative to tubularportions (706, 710) and includes a generally circular aperture (723),which is also positioned coaxially relative to first and second tubularportions (706, 710). Flange (722) includes a proximal side (724) facingin a direction opposite of arrow (713) syringe adapter (702) and adistal side (726) in the direction of arrow (713). Flange (722) isgenerally hexagonal and includes six edges (528), such that flange (722)is shaped to complement flange (622). Flange (722) includes an aperture(723) that is coaxial with tubular member (712) and is configured toreceive tubular member (640) of syringe (602), as discussed in furtherdetail below. A support member (730) connects flange (722) with tubularportions (706, 710). Support member (730) includes a first portion (732)that extends along a plane that is perpendicular to axis (707), andopposing legs (734) extending perpendicular to first portion (732) andparallel to axis (707) in the direction of arrow (713). In the presentexample, syringe adapter (502) is a single unitary body, but in otherexamples may comprise multiple portions coupled together.

As shown best in FIGS. 17 and 21A-C, annular recesses (714) each receivesealing elements, which in the present example include an O-ring (750)received in each of the annular recesses (714). Tubular portion (710) issized and configured to be received in second opening (648) of tubularmember (640) once, for example, the plunger rod (not shown) is decoupledfrom the piston (not shown). O-rings (750) are configured to provide afluid tight seal between lumen (650) of tubular member (640) and syringeadapter (702) to prevent the escape of fluid pressure from second end(648) of tubular member (640). As discussed in more detail below,proximal tubular portion (706) of syringe adapter (702) may be coupledto a source of pressurized fluid medium and distal tubular portion (710)of syringe adapter (702) may be received in second end (648) of tubularmember (640). Therefore, a pressurized fluid medium may be communicatedto lumen (650) of tubular member (640) via adapter (702) and cause theadvancement or retraction of the piston (not shown) within tubularmember (640) to cause fluid to be dispensed from or drawn into tubularmember (640), respectively.

As shown in FIGS. 26A-27C, in order to assemble assembly (600), anoperator inserts distal tubular portion (710) of syringe adapter (702)into opening (648) of tubular member (640), in the absence of plungerrod (436), such that flange (722) of syringe adapter (702) is adjacentto or generally abuts flange (622) of syringe (602). In the presentexample, O-rings (750) are sized and configured such that they arecompressed to a smaller cross-sectional dimension between annularrecesses (714) and lumen (650). O-rings (750) of the present example mayinclude a lubricious coating such as silicone in order to reduce thefriction between O-rings (750) and lumen (650) during insertion ofsyringe adapter (702) into syringe (602). Insertion of distal tubularportion (710) into tubular member (640) results in a transition from theconfiguration shown in FIGS. 26A and 27A to the configuration shown inFIGS. 26B and 27B.

The operator may then direct engagement collar (804) into engagementwith syringe (602) and syringe adapter (702) in a substantially similarmanner as described above with respect to engagement collar (504),syringe (402), and syringe adapter (502). This will result in theconfiguration shown in FIGS. 26C and 27C. Engagement collar (804) isconfigured to operate substantially similar to engagement collar (504),except that the general shape of engagement collar (804) has beenadapted for use with the hexagonal shape of flanges (622, 722). Thus,the operator directs engagement collar (802) relative to syringe (602)and syringe adapter (702) such that a portion of flanges (622, 722)enter into a U-shaped cavity. Ramps (860 a, 862 a) and ramps (860 c, 862c) of engagement collar (only 860 a, 862 a, 860 c, 862 c are shown)provide a compressive force on flanges (622, 722) such that flanges maybe urged closer together in a substantially similar manner to flanges(422, 522) as discussed above. Suitable other ways in which assembly(600) may be configured will be apparent to persons skilled in the artin view of the teachings herein.

After reaching the state shown in FIGS. 26C and 27C, the operator maycouple a flexible tube with barbed connection feature (708) to therebycouple assembly (600) with a source of a pressurized medium (e.g., air,saline) as described below. The operator may further couple threadedportion (616) of syringe (602) with instrument (1000) to therebydispense the fluid from syringe (602) to instrument (1000) as alsodescribed below.

VII. Exemplary Powered Injection System for Delivering TherapeuticFluids for Treatment of an Ocular Condition

FIG. 28 shows an exemplary pressure control delivery system (900) fordelivering one or more fluids during a procedure to treat an ocularcondition, such as the subretinal delivery of therapeutic agent (341)described above with respect to FIGS. 9A-11C. In the present example,system (900) comprises a fluid medium source (901) that is coupled witha fluid pump (902) and a pressure regulator (903). In some examples,fluid medium source (901) comprises saline. In some other examples, airis used as the pressurized fluid medium. Other suitable fluid media thatmay be used will be apparent to those of ordinary skill in the art inview of the teachings herein. It should be understood that pump (902) isoperable to pressurize the fluid medium and regulator (903) is operableto regulate the fluid pressure of the pressurized fluid medium that isoutput from pump (902). Various suitable forms that pump (902) andregulator (903) may take will be apparent to those of ordinary skill inthe art in view of the teachings herein.

Pressure regulator (903) comprises pneumatic connectors (e.g., CPC SMSSeries connectors) with barbed fittings (904, 906). Barbed fitting (904)is coupled with assembly (500) via a tube (908). In particular, tube(908) is secured to barbed connection feature (508). Thus, pressurizedfluid medium may be delivered from pump (902) to assembly (500) viaregulator (903) and tube (908) to thereby dispense fluid from syringe(402). Barbed fitting (906) is coupled with assembly (600) via a tube(910). In particular, tube (910) is secured to assembly (600) via barbedconnection feature (708). Thus, pressurized fluid medium may bedelivered from pump (902) to assembly (600) via regulator (903) and tube(910) to thereby dispense fluid from tubular member (640) via syringe(602).

Instrument (1000) is coupled with both assemblies (500, 600) via tubes(918, 920). In particular, instrument (1000) is coupled with assembly(500) via tube (918); and with assembly (600) via tube (920). Tube (918)is coupled with assembly (500) via threaded portion (416). Tube (920) iscoupled with assembly (600) via threaded portion (616). As noted above,instrument (1000) may be configured and operable like instruments (10,2010) described above. Tubes (918, 920) of system (900) may thus serveas tubes (64) or tubes (2090, 2091) as described above.

In an exemplary method of operation, each assembly (500, 600) is filledwith fluid (e.g., bleb fluid (340), therapeutic agent (341), etc.), theair is purged from each assembly (500, 600), and the remaining amount offluid is reduced to the predetermined amount (e.g., using tab (402),etc.) as described above. Assemblies (500, 600) are then coupled withpressure regulator (903) via tubes (908, 910); and with instrument(1000) via tubes (918, 920). Once instrument (1000) has beenappropriately positioned with respect to a patient, such that instrument(1000) is positioned to deliver fluid to a target site (e.g., thesubretinal space) in the patient, system (900) may be activated. Inparticular, fluid pump (902) may be activated to pressurize the fluidmedium from source (901); regulator (903) may regulate the pressure ofthe fluid output from fluid pump (902); and the pressurized fluid mediummay reach each assembly (500, 600) via tubes (908, 910). At this stage,the pressure within each assembly (500, 600) will be effectivelypressurized due to the pressurized fluid medium from source (901) actingagainst the proximal face of piston (434) in each assembly (500, 600).

In the present example, instrument (1000) includes a valve assembly thatis in fluid communication with tubes (918, 920). This valve assemblyenables instrument (1000) to deliver the pressurized fluid from eachassembly (500, 600) at a selected time and in a selected sequence (e.g.,to ensure that bleb fluid (340) is delivered first; then therapeuticagent (341)). For instance, instrument (1000) may include an integralvalve assembly that is configured and operable in accordance with atleast some of the teachings of U.S. patent application Ser. No.14/619,256, entitled “Method and Apparatus for Subretinal Administrationof Therapeutic Agent,” filed Feb. 11, 2015, issued as U.S. Pat. No.10,226,379 on Mar. 12, 2019, the disclosure of which is incorporated byreference herein. In addition or in the alternative to instrument (1000)having an integral valve assembly, system (900) may also include one ormore valves. For instance, system (900) may include one or more valvesinterposed between assemblies (500, 600) and instrument (1000). Inaddition or in the alternative, system (900) may include one or morevalves interposed between regulator (903) and assemblies (500, 600).Other suitable ways in which valves may be incorporated into instrument(1000) and/or system (900) will be apparent to those of ordinary skillin the art in view of the teachings herein.

In some examples, assembly (500) contains bleb fluid (340), such thatsystem (900) is operable to deliver bleb fluid (340) from assembly (500)to instrument (1000) via tube (918); and assembly (600) containstherapeutic agent (341), such that system (900) is operable to delivertherapeutic agent (341) from assembly (600) to instrument (1000) viatube (920). In some other examples, assembly (500) contains therapeuticagent (341), such that system (900) is operable to deliver therapeuticagent (341) from assembly (500) to instrument (1000) via tube (918); andassembly (600) contains bleb fluid (340), such that system (900) isoperable to deliver bleb fluid (340) from assembly (600) to instrument(1000) via tube (920). It should therefore be understood that system(900) may be used in combination with instrument (1000) to perform thesubretinal delivery of bleb fluid (340) and therapeutic agent (341)described above with respect to FIGS. 9A-11C. Other suitable ways inwhich system (900) may be used, with or without instrument (1000), willbe apparent to those of ordinary skill in the art in view of theteachings herein.

VIII. Exemplary Manual Injection System with Spacers for ControllingPriming and Delivered Fluid Volume

FIGS. 29-36G depict another exemplary fluid delivery assembly (1100)that may be used to store and deliver predetermined amount of fluids,such as bleb (340) fluid and therapeutic agent (341) fluid as describedabove, to a subretinal space in a precise and consistent manner via aninstrument (e.g., instrument (10, 2010)). As discussed in more detailbelow, this system may be fluidly coupled with an instrument (1000),which may be configured and operable just like instrument (10, 2010)described above. Alternatively, instrument (1000) may have any othersuitable configuration and may be configured for use with fluid deliveryassembly (1100) in any suitable procedure calling for delivery of apredetermined amount of fluid.

Fluid delivery assembly (1100) of the present example comprises asyringe assembly (1200), a first spacer (1300), a second spacer (1400),and a third spacer (1500). As best seen in FIGS. 30 and 36A-36B, syringeassembly (1200) comprises a barrel (1210) and a plunger (1220). Barrel(1210) of the present example comprises a port (1212) and a flange(1214). Plunger (1220) comprises a shaft (1222) and a thumb flange(1224). Plunger (1220) also includes a piston (not shown) that isslidably disposed in barrel (1210) to provide a variable volume withinbarrel (1210), in accordance with conventional syringe construction andoperability. It should therefore be understood that plunger (1220) maybe reciprocated relative to barrel (1210) in order to draw fluid intobarrel (1210) or expel fluid from barrel (1210).

As shown in FIGS. 29-30, 35, and 36C, spacers (1300, 1400, 1500) areconfigured to nest with each other and syringe assembly (1200). As bestseen in FIG. 31, first spacer (1300) comprises an upper sleeve (1310), alower sleeve (1320), and a pair of outwardly extending finger grips(1330). Sleeves (1310, 1320) each generally define a “U” shape. Firstspacer (1310) further defines a channel (1340), which is configured toreceive flange (1214) of barrel (1210) as shown in FIGS. 29-30, 35, and36C-36G. When first spacer (1300) is coupled with barrel (1210), the fitbetween channel (1340) and flange (1214) prevents relative longitudinalmovement between first spacer (1300) and barrel (1210). In addition,when first spacer (1300) is coupled with barrel (1210), upper sleeve(1310) extends upwardly relative to flange (1214); while lower sleeve(1320) partially encompasses barrel (1210). In some versions, lowersleeve (1320) provides a snug fit about barrel (1210) such that firstspacer (1300) releasably grips onto barrel (1210). In addition or in thealternative, channel (1340) may be configured to provide a snap fit,snug fit, and/or some other kind of releasable gripping engagement withflange (1214) to thereby enable first spacer (1300) to releasably griponto barrel (1210). Referring back to FIG. 31, upper sleeve (1310)further includes an upper ledge (1312), a pair of engagement ridges(1314), and a pair of engagement edges (1316). Each of these featureswill be described in greater detail below.

As best seen in FIGS. 32-33, second spacer (1400) comprises a sleeve(1410) and a grip (1430) extending laterally from sleeve (1410). Sleeve(1410) defines a “U” shape and includes an upper ledge (1412), a pair ofengagement ridges (1414), and a pair of engagement channels (1440).Sleeve (1410) further includes a set of latches (1450). Second spacer(1400) is configured to fit around first spacer (1300), as shown inFIGS. 29-30, 35, and 36C-36E. In particular, sleeve (1410) of secondspacer (1400) is configured to encompass upper sleeve (1310) of firstspacer (1300), with engagement ridges (1314) fitting in engagementchannels (1440). When engagement ridges (1314) are fully seated inengagement channels (1440), latches (1450) engage engagement ridges(1314) to provide a snap fit between second spacer (1400) and firstspacer (1300). Of course, any other suitable structures and techniquesmay be used to releasably secure second spacer (1400) to first spacer(1300). As best seen in FIG. 35, spacers (1300, 1400) are configuredsuch that upper ledge (1412) is positioned higher than upper ledge(1312) when spacers (1300, 1400) are secured together.

As best seen in FIG. 34, third spacer (1500) comprise a sleeve (1510)and a grip (1530) extending laterally from sleeve (1510). Sleeve (1510)defines a “U” shape and includes an upper ledge (1512) and a pair ofengagement channels (1540). Grip (1530) also defines a channel (1532).Third spacer (1500) is configured to fit around second spacer (1300), asshown in FIGS. 29-30, 35, and 36C. In particular, sleeve (1510) of thirdspacer (1500) is configured to encompass sleeve (1410) of second spacer(1400), with engagement ridges (1414) fitting in channels engagement(1540). Channel (1532) of grip (1530) is configured to accommodate grip(1430) of second spacer (1400) when spacers (1400, 1500) are coupledtogether. When engagement ridges (1414) are fully seated in engagementchannels (1540), ridges (1414) and channels (1540) may cooperate toprovide a snap fit between third spacer (1500) and second spacer (1400).Of course, any other suitable structures and techniques may be used toreleasably secure third spacer (1500) to second spacer (1400). As bestseen in FIG. 35, spacers (1400, 1500) are configured such that upperledge (1512) is positioned higher than upper ledge (1412) when spacers(1400, 1500) are secured together. As also seen in FIG. 35, sleeves(1310, 1410, 1510) are all sized to enable shaft (1222) of plunger(1220) to translate freely relative to sleeves (1310, 1410, 1510).However, ledges (1312, 1412, 1512) are configured to engage thumb flange(1224) of plunger (1220) to thereby restrict movement of plunger (1220)as will be described in greater detail below.

FIGS. 36A-36G show an exemplary sequence of acts that may be performedusing the components of fluid delivery assembly (1100). In particular,FIG. 36A shows syringe assembly (1200) coupled with a fluid source(1600), with plunger (1220) fully advanced relative to barrel (1210).Port (1212) may be coupled with fluid source (1600) via flexible tubingand/or via any other suitable structure or relationship as will beapparent to those of ordinary skill in the art in view of the teachingsherein. It should be understood that fluid source (1600) may includefluid for forming leading bleb (340), therapeutic agent (341), and/orany other suitable fluid.

Once port (1212) is placed in fluid communication with fluid source(1600), plunger (1220) is retracted from barrel (1210) as shown in FIG.36B, thereby drawing fluid from fluid source (1600) into barrel (1210).Once fluid has been drawn into barrel (1210), barrel (1210) is decoupledfrom fluid source (1600), and spacers (1300, 1400, 1500) are secured tosyringe assembly (1200) as shown in FIG. 36C. With spacers (1300, 1400,1500) secured to syringe assembly (1200), plunger (1220) is advanceduntil thumb flange (1224) engages upper ledge (1512) of third sleeve(1510), as also shown in FIG. 36C. Engagement between thumb flange(1224) and upper ledge (1512) arrests further movement of plunger (1220)into barrel (1210). It should be understood that during movement ofplunger (1220) from the position shown in FIG. 36B to the position shownin FIG. 36C, air and some fluid may be expelled from barrel (1210). Inthe present example, barrel (1210) contains no air and only containsfluid from fluid source (1600) in the state shown in FIG. 36C. Thus,fluid delivery assembly (1100) may be considered as being in a primedstate at the stage shown in FIG. 36C.

With fluid delivery assembly (1100) in the primed state, the operatormay remove third spacer (1500) from second spacer (1400), resulting inthe configuration shown in FIG. 36D. At this stage, a small gap (g₁) isdefined between upper ledge (1412) of second spacer (1400) and theunderside of thumb flange (1224). This gap (g₁) corresponds to thedistance between upper ledges (1412, 1512) when spacers (1400, 1500) arecoupled together. At this stage, port (1212) is also coupled withinstrument (1000). As noted above, instrument (1000) may be configuredand operable just like instrument (10, 2010) described above.Alternatively, instrument (1000) may take any other suitable form. Itshould also be understood that port (1212) may be coupled withinstrument (1000) via flexible tubing and/or using any other suitablestructures or techniques.

Once third spacer (1500) has been removed from second spacer (1400) andport (1212) has been coupled with instrument (1000), the operator mayadvance plunger (1220) further to the position shown in FIG. 36E. Inparticular, plunger (1220) is advanced until thumb flange (1224) engagesupper ledge (1412) of second sleeve (1410). Engagement between thumbflange (1224) and upper ledge (1412) arrests further movement of plunger(1220) into barrel (1210). It should be understood that during movementof plunger (1220) from the position shown in FIG. 36D to the positionshown in FIG. 36E, air and/or some fluid may be expelled from instrument(1000). In the present example, instrument (1000) contains no air andonly contains fluid from fluid barrel (1210) (which is fluid from fluidsource (1600)) in the state shown in FIG. 36E. Thus, instrument (1000)may be considered as being in a primed state at the stage shown in FIG.36E. In some versions, the steps described above with respect to FIGS.36A-36E are performed by a nurse; while the subsequent steps describedbelow are performed by a surgeon. Of course, this is just one merelyillustrative example. Any of the steps described herein may be performedby any suitable personnel.

With instrument (1000) in the primed state, the operator may removesecond spacer (1400) from second spacer (1300), resulting in theconfiguration shown in FIG. 36F. At this stage, a small gap (g₂) isdefined between upper ledge (1312) of first spacer (1300) and theunderside of thumb flange (1224). This gap (g₂) corresponds to thedistance between upper ledges (1312, 1412) when spacers (1300, 1400) arecoupled together. When instrument (1000) is positioned to deliver fluidto the patient (e.g., in the state shown in FIGS. 9H, 10E, and 11A; orin the state shown in FIGS. 9I, 10F, and 11B), the operator may thenadvance plunger (1220) further to the position shown in FIG. 36G. Inparticular, plunger (1220) is advanced until thumb flange (1224) engagesupper ledge (1312) of upper sleeve (1310). Engagement between thumbflange (1224) and upper ledge (1312) arrests further movement of plunger(1220) into barrel (1210). It should be understood that during movementof plunger (1220) from the position shown in FIG. 36F to the positionshown in FIG. 36G, fluid will be delivered to the patient via instrument(1000), in response to movement of plunger (1220) from the positionshown in FIG. 36F to the position shown in FIG. 36G.

It should also be understood that the volume of fluid delivered to thepatient via instrument (1000) during the transition from the state shownin FIG. 36F to the state shown in FIG. 36G will be fixed andpredetermined. In particular, the volume of fluid delivered to thepatient via instrument (1000) will be a function of the distancetraversed by plunger (1220) during movement from the position shown inFIG. 36F to the position shown in FIG. 36G. This distance traveled isrepresented by the gap distance (g₂). This gap distance (g₂) ispredefined as the distance between upper ledges (1312, 1412) whenspacers (1300, 1400) are coupled together. Thus, the operator mayconsistently and confidently deliver the appropriate volume of fluid tothe patient via instrument (1000). In the present example, the volume offluid delivered during the transition from the state shown in FIG. 36Fto the state shown in FIG. 36G is 50 μL. Alternatively, any othersuitable volume may be provided.

It should be understood from the foregoing that the configuration ofthird spacer (1500) provides a predefined priming volume, such thatthird spacer (1500) may be regarded as a priming spacer; while theconfiguration of second spacer (1400) provides a predefined dosagevolume, such that second spacer (1400) may be regarded as a dosagespacer. In some instances, the operator may be presented with a set ofdifferent spacers (1400), with the different spacers (1400) providingdifferent heights between upper ledges (1312, 1412) to thereby providedelivery of different volumes of fluid. The operator may select the mostappropriate second spacer (1400) from this set based on considerationssuch as the particular fluid being delivered, the medical conditionbeing treated, patient physiology, etc. The operator may then use theselected second spacer (1400) to assembly fluid delivery system (1100)as shown in FIG. 36C and carry out the rest of the steps as describedabove with reference to FIGS. 36C-36G. In any case, there may be someamount of fluid that is left in barrel (1210) after reaching the stageshown in FIG. 36G. This excess fluid may simply be disposed of orotherwise dealt with.

IX. Exemplary Combinations

The following examples relate to various non-exhaustive ways in whichthe teachings herein may be combined or applied. It should be understoodthat the following examples are not intended to restrict the coverage ofany claims that may be presented at any time in this application or insubsequent filings of this application. No disclaimer is intended. Thefollowing examples are being provided for nothing more than merelyillustrative purposes. It is contemplated that the various teachingsherein may be arranged and applied in numerous other ways. It is alsocontemplated that some variations may omit certain features referred toin the below examples. Therefore, none of the aspects or featuresreferred to below should be deemed critical unless otherwise explicitlyindicated as such at a later date by the inventors or by a successor ininterest to the inventors. If any claims are presented in thisapplication or in subsequent filings related to this application thatinclude additional features beyond those referred to below, thoseadditional features shall not be presumed to have been added for anyreason relating to patentability.

Example 1

A system for storing and delivering a predetermined amount of fluid, thesystem comprising: (a) a syringe defining a longitudinal axis,comprising: (i) a barrel comprising: (A) a first end, (B) a second end,and (C) a lumen extending between the first and second ends, (ii) afirst flange disposed at the second end and extending away from thelongitudinal axis, and (iii) a plunger assembly configured to bereceived in the lumen of the barrel and move relative to the lumen todraw fluid into and dispense fluid from the syringe, wherein the plungerassembly comprises: (A) a piston, (B) a plunger rod comprising a firstend and a second end, wherein the first end of the plunger rod iscoupled with the piston, wherein the plunger rod comprises a secondflange at the second end of the plunger rod; and (b) a first stopfeature, wherein the first stop feature is removably couplable to atleast one of the barrel, the first flange, or the plunger assembly,wherein the first stop feature is configured to restrict advancement ofthe plunger assembly relative to the barrel to prevent the plungerassembly from advancing beyond a predetermined distance from either aportion of the first flange or a portion of the barrel.

Example 2

The system of Example 1, further comprising a second stop feature,wherein the second stop feature is removably coupleable to the firststop feature, wherein the second stop feature is configured to restrictadvancement of the plunger assembly relative to the barrel to preventthe plunger assembly from advancing beyond a second predetermineddistance from either a portion of the first flange or a portion of thebarrel.

Example 3

The system of any one or more of Examples 1 through 2, wherein theplunger rod is threadably coupled with the piston.

Example 4

The system of Example 3, wherein the first end of the plunger rodcomprises a threaded portion, wherein the piston comprises a threadedaperture configured to receive the threaded portion of the plunger rod.

Example 5

The system of any one or more of Examples 1 through 4, wherein the firststop feature comprises an engagement portion, wherein a portion of theengagement portion has a shape that is complementary to across-sectional profile of the plunger rod.

Example 6

The system of any one or more of Examples 1 through 5, wherein the firststop feature is configured to prevent distal movement of the plungerassembly relative to the barrel when the second flange is apredetermined distance from the first flange.

Example 7

The system of Example 6, wherein the first stop feature is configured toabut the second flange and the first flange when the second flange ispositioned at the predetermined distance from the first flange.

Example 8

The system of any one or more of Examples 1 through 7, furthercomprising an adapter, wherein the plunger rod is configured to decouplefrom the piston, wherein the adapter is configured to be received in thesecond end of the barrel in the absence of plunger rod, wherein theadapter is configured to fluidly couple the syringe with a source ofpressurized fluid to move the piston within the lumen.

Example 9

The system of Example 8, wherein the adapter comprises a first tubularportion, a second tubular portion, and a third flange between the firstand second tubular portions, wherein the first tubular portion isconfigured to be received in the second end of the barrel in the absenceof plunger rod, wherein the third flange is configured to abut the firstflange when the first tubular portion is received in the second end ofbarrel.

Example 10

The system of Example 9, further comprising a collar, wherein the collaris configured to secure the adapter to the syringe.

Example 11

The system of Example 10, wherein the collar is configured to envelop atleast a portion of the first flange and at least a portion of the thirdflange.

Example 12

The system of any one or more of Examples 10 through 11, wherein thecollar further comprises a cavity configured to receive at least aportion of the first flange and at least a portion of the third flange.

Example 13

The system of Example 12, wherein the collar further comprises a rampfeature, wherein the ramp feature is configured to urge the first andthird flanges toward each other when the first and third flanges aredirected into the cavity.

Example 14

The system of Example 13, wherein the ramp feature includes a taperedleading portion.

Example 15

The system of any one or more of Examples 10 through 14, furthercomprising: (a) a pump operable to provide a pressurized fluid medium;and (b) a pressure regulator, wherein the pressure regulator is in fluidcommunication with the pump and is thereby operable to regulate thepressure of the pressurized fluid medium provided by the pump, whereinthe pressure regulator is further in communication with the syringe suchthat the syringe is operable to receive the pressurized fluid medium.

Example 16

A method of filling and priming a syringe, wherein the syringe defines alongitudinal axis, wherein the syringe comprises a barrel and a plungerassembly including a plunger rod removably coupled to a piston, themethod comprising: (a) fluidly coupling the barrel with a source offluid; (b) moving the plunger assembly relative to the barrel in a firstdirection along the longitudinal axis to draw fluid into the barrel; (c)removably coupling a stop member to a portion of the syringe or theplunger rod; (d) moving the plunger assembly relative to the barrel in asecond direction that is opposite to the first direction until the stopmember prevents further the movement of the plunger assembly in thesecond direction; and (e) decoupling the plunger rod from the piston andremoving the plunger rod from the barrel.

Example 17

The method of Example 16, further comprising decoupling the stop memberfrom the syringe or the plunger rod.

Example 18

The method of any one or more of Examples 16 through 17, whereindecoupling the plunger rod from the piston further comprises rotatingthe plunger rod relative to the plunger to release a threaded engagementbetween the plunger rod and the piston.

Example 19

The method of any one or more of Examples 16 through 18, furthercomprising: (a) fluidly coupling the syringe to a source of pressurizedfluid; and (b) directing the pressurized fluid into the syringe toadvance the piston further in the second direction.

Example 20

A method of operating a syringe, wherein the syringe defines alongitudinal axis, wherein the syringe comprises a barrel including aproximal end and a distal end, wherein the syringe further comprises aplunger assembly configured to be received in the proximal end of thebarrel, wherein the plunger assembly comprises a plunger rod removablycoupled to a piston, the method comprising: (a) fluidly coupling thedistal end of the barrel with a source of fluid; (b) moving the plungerassembly proximally relative to the barrel along the longitudinal axisto draw fluid into the barrel, wherein the fluid is received distal tothe piston; (c) priming the syringe to purge air from the syringe; (d)decoupling the plunger rod from the piston and removing the plunger rodfrom the barrel; (e) fluidly coupling the barrel to a source ofpressurized fluid at the proximal end of the barrel; and (f) directingpressurized fluid into the barrel to advance the piston distally,wherein the act of directing pressurized fluid into the barrel comprisesdirecting the pressurized fluid proximal to the piston.

X. Miscellaneous

It should be understood that any of the versions of the instrumentsdescribed herein may include various other features in addition to or inlieu of those described above. By way of example only, any of thedevices herein may also include one or more of the various featuresdisclosed in any of the various references that are incorporated byreference herein.

It should be understood that any one or more of the teachings,expressions, embodiments, examples, etc. described herein may becombined with any one or more of the other teachings, expressions,embodiments, examples, etc. that are described herein. Theabove-described teachings, expressions, embodiments, examples, etc.should therefore not be viewed in isolation relative to each other.Various suitable ways in which the teachings herein may be combined willbe readily apparent to those of ordinary skill in the art in view of theteachings herein. Such modifications and variations are intended to beincluded within the scope of the claims.

It should be appreciated that any patent, publication, or otherdisclosure material, in whole or in part, that is said to beincorporated by reference herein is incorporated herein only to theextent that the incorporated material does not conflict with existingdefinitions, statements, or other disclosure material set forth in thisdisclosure. As such, and to the extent necessary, the disclosure asexplicitly set forth herein supersedes any conflicting materialincorporated herein by reference. Any material, or portion thereof, thatis said to be incorporated by reference herein, but which conflicts withexisting definitions, statements, or other disclosure material set forthherein will only be incorporated to the extent that no conflict arisesbetween that incorporated material and the existing disclosure material.

Versions described above may be designed to be disposed of after asingle use, or they can be designed to be used multiple times. Versionsmay, in either or both cases, be reconditioned for reuse after at leastone use. Reconditioning may include any combination of the steps ofdisassembly of the device, followed by cleaning or replacement ofparticular pieces, and subsequent reassembly. In particular, someversions of the device may be disassembled, and any number of theparticular pieces or parts of the device may be selectively replaced orremoved in any combination. Upon cleaning and/or replacement ofparticular parts, some versions of the device may be reassembled forsubsequent use either at a reconditioning facility, or by an operatorimmediately prior to a procedure. Those skilled in the art willappreciate that reconditioning of a device may utilize a variety oftechniques for disassembly, cleaning/replacement, and reassembly. Use ofsuch techniques, and the resulting reconditioned device, are all withinthe scope of the present application.

By way of example only, versions described herein may be sterilizedbefore and/or after a procedure. In one sterilization technique, thedevice is placed in a closed and sealed container, such as a plastic orTYVEK bag. The container and device may then be placed in a field ofradiation that can penetrate the container, such as gamma radiation,x-rays, or high-energy electrons. The radiation may kill bacteria on thedevice and in the container. The sterilized device may then be stored inthe sterile container for later use. A device may also be sterilizedusing any other technique known in the art, including but not limited tobeta or gamma radiation, ethylene oxide, or steam.

Having shown and described various embodiments of the present invention,further adaptations of the methods and systems described herein may beaccomplished by appropriate modifications by one of ordinary skill inthe art without departing from the scope of the present invention.Several of such potential modifications have been mentioned, and otherswill be apparent to those skilled in the art. For instance, theexamples, embodiments, geometrics, materials, dimensions, ratios, steps,and the like discussed above are illustrative and are not required.Accordingly, the scope of the present invention should be considered interms of the following claims and is understood not to be limited to thedetails of structure and operation shown and described in thespecification and drawings.

We claim:
 1. A method of delivering fluid to the subretinal space of aneye, the method comprising: (a) coupling a powered pressure controldelivery system with a first source of fluid; (b) coupling the firstsource of fluid with an instrument, the instrument comprising a needle,wherein the needle comprises a distal end, wherein the instrumentfurther comprises a cannula slidably housing the needle; (c) accessing aspace between a retina and a choroid of an eye with the distal end ofthe needle, wherein accessing the space between the retina and thechoroid of the eye comprises advancing the cannula between a sclera andthe choroid of the eye such that the cannula conforms to a curvature ofthe eye; (d) advancing the needle through the choroid while the cannularemains positioned between the sclera and the choroid; and (e)activating the powered pressure control delivery system so that thepowered pressure control delivery system drives a first fluid from thefirst source of fluid through the distal end of the needle and into thespace between the retina and choroid of the eye.
 2. The method of claim1, wherein the powered pressure control delivery system comprises amedium source and a pump, wherein activating the powered pressurecontrol delivery system activates the pump to drive the medium source.3. The method of claim 2, wherein activating the powered pressurecontrol delivery system drives the medium source to drive the firstfluid of the first source of fluid through the distal end of the needle.4. The method of claim 3, wherein the powered pressure control deliverysystem comprises a pressure regulator positioned between the pump andthe instrument, wherein activating the powered pressure control deliverysystem further comprises utilizing the pressure regulator to regulate afluid pressure of the medium source.
 5. The method of claim 4, whereinthe first source of fluid is housed within a first syringe comprising afirst piston, wherein activating the powered pressure control deliverysystem further comprises utilizing the medium source to actuate thefirst piston to thereby drive the first source of fluid.
 6. The methodof claim 4, wherein the pressure regulator comprises a pneumaticconnector.
 7. The method of claim 1, further comprising coupling asecond source of fluid with the needle.
 8. The method of claim 7,wherein coupling the second source of fluid with the needle is performedwhile the first source of fluid is coupled with the instrument.
 9. Themethod of claim 8, wherein activating the powered pressure controldelivery system includes utilizing the powered pressure control deliverysystem to drive a second fluid of the second source of fluid through thedistal end of the needle and into the space between the retina andchoroid of the eye.
 10. The method of claim 9, wherein activating thepowered pressure control delivery system includes driving a second fluidof the second source of fluid through the distal end of the needle afterdriving the first fluid through the distal end of the needle.
 11. Themethod of claim 10, wherein the second source of fluid is housed withina second syringe comprising a second piston, wherein activating thepowered pressure control delivery system further comprises utilizing themedium source to actuate the second piston to thereby drive the secondsource of fluid.
 12. The method of claim 11, the first fluid comprises aleading bleb fluid.
 13. The method of claim 12, wherein the second fluidcomprises a therapeutic agent.
 14. The method of claim 1, whereinaccessing the space between the retina and the choroid of the eyefurther comprises advancing the needle distally past the cannula topenetrate the choroid.
 15. The method of claim 14, further comprisingtenting the choroid with the needle.
 16. The method of claim 15, whereinactivating the powered pressure control delivery system occurs aftertenting the choroid with the needle.
 17. The method of claim 1, whereinaccessing the space between the retina and the choroid of the eyefurther comprises inserting the cannula through an incision formed inthe sclera into a space between the sclera and the choroid such that thecannula is oriented tangentially relative to the incision prior toadvancing the cannula between the sclera and the choroid.
 18. A methodof delivering fluid to the subretinal space of an eye, the methodcomprising: (a) coupling a source of fluid with both a powered pressurecontrol delivery system and a needle, wherein the needle comprises adistal end; (b) accessing a space between a retina and a choroid of aneye with the distal end of the needle, wherein accessing the spacebetween the retina and the choroid of the eye comprises piercing thechoroid with the distal end of the needle; and (c) activating thepowered pressure control delivery system so that the powered pressurecontrol delivery system automatically drives a fluid along a fluid pathfrom the source of fluid through the distal end of the needle and intothe space between the retina and choroid of the eye thereby expandingthe space, wherein at least a portion of the fluid path conforms to acurvature of the eye.
 19. The method of claim 18, further comprisingremoving the distal end of the needle from the space.
 20. A method ofdelivering fluid to the subretinal space of an eye, the methodcomprising: (a) coupling a powered pressure control delivery system witha first source of fluid; (b) coupling the powered pressure controldelivery system with a second source of fluid; (c) coupling the firstsource of fluid and the second source of fluid with an instrumentcomprising a needle, wherein the needle comprises a distal end; (d)accessing a space between a retina and a choroid of an eye with thedistal end of the needle, wherein accessing the space between the retinaand the choroid of the eye comprises piercing the choroid with thedistal end of the needle; and (e) activating the powered pressurecontrol delivery system so that the powered pressure control deliverysystem drives a first fluid along a fluid path from the first source offluid through the distal end of the needle and into the space betweenthe retina and choroid of the eye and then subsequently drives a secondfluid along the fluid path from the second source of fluid through thedistal end of the needle, wherein at least a portion of the fluid pathconforms to a curvature of the eye.